Dissertations / Theses: 'Neuroprotective agents'

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Nilsson, Olov. "Cannabinoids as neuroprotective agents : a mechanistic study." Doctoral thesis, Umeå : Umeå universitet, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-873.

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Badenhorst, Hester Elizabeth. "Antihistamines as neuroprotective agents / Hester Elizabeth Badenhorst." Thesis, North-West University, 2004. http://hdl.handle.net/10394/95.

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Biomolecules are continuously exposed to potentially harmful oxidative stress as a consequence of free radical formation. Increased free radical generation has been associated with aging as well as neurodegenerative disorders. Antioxidants affect processes associated with oxidative stress by quenching free radicals and acting as oxygen scavengers. Parkinson's disease results from a deficiency in the neurotransmitter, dopamine and it is also evident that damage caused by free radicals play an important role in the progression of this neurodegenerative disorder. The histamine HI antagonist, diphenhydramine is used to treat mild cases of Parkinson's disease and cimetidine can scavenge hydroxyl radicals. The histamine H3 antagonists are known to promote the release of dopamine. Together with a free radical scavenging activity, these compounds might have a dual therapeutic effect in the reduction of the progression of Parkinson's disease. The aim of this study was thus to determine whether histamine antagonists could act as free radical scavengers and to compare the results with aspirin, a known free radical scavenger. Ibuprofen was included to compare the free radical scavenging activities of aspirin to another non-steroidal anti-inflammatory drug. The free radical scavenging activities of the following compounds were determined and compared: diphenhydramine; cimetidine; roxatidine; clobenpropit; impentarnine; thioperamide; aspirin and ibuprofen. The ORAC assay was used to determine whether the test compounds were able to scavenge peroxyl radicals and the FRAP assay was used to determine the reducing abilities of the compounds. No meaningll results were obtained from these two assays, suggesting that the compounds were not able to act as direct antioxidants or as peroxyl radical scavengers. The comet assay was used to determine whether the compounds were able to reduce oxidative damage after MPTP administration. No damage was however obtained after a single dose of MPTP and it is suggested that one year old mice and chronic rather than acute treatment is used. Using a cyanide model to induce neurotoxic effects in rat brain homogenates, the neuroprotective properties of the histamine antagonists were examined and compared to aspirin. Superoxide anion levels and malondialdehyde concentrations were assessed using the nitrobluetetrazolium and lipid peroxidation assays. Clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. At a concentration of lmM, these two histamine Hj antagonists reduced lipid peroxidation to values lower than that of the control. Impentamine reduced lipid peroxidation at all concentrations used and superoxide anion generation at a concentration of 1mM. Diphenhydramine (0.25 and 0.5mM) significantly reduced both variables at lower concentrations. Cimetidine (1mM) was able to reduce superoxide anion generation and significantly reduced lipid peroxidation at all concentrations Abstract used. Roxatidine (0.5mM and 1mM) significantly reduced the rise in superoxide anion generation and significantly reduced malondialdehyde concentration in a dose dependent manner. Ibuprofen significantly decreased superoxide anions in a dose dependant manner and lipid peroxidation at a concentration of 1mM. In the lipid peroxidation assay, all the drugs compared favourably to aspirin. The in vivo free radical scavenging effects of the selected compounds were also examined with the nitroblue tetrazoliurn and lipid peroxidation assays. MPP' was used to induce a Parkinsonian like condition. Diphenhydramine, ibuprofen, thioperamide and clobenpropit significantly reduced free radical generation in both assays. Thioperamide and clobenpropit were able to reduce lipid peroxidation and superoxide anion generation to values lower than that of the control, suggesting that these two compounds could be able to attenuate normal free radical processes in the brain. Cimetidine did not have the expected in vivo scavenging effects and it is suggested that blood-brain barrier permeability might play a role. All the compounds, except diphenhydramine had significantly lower in vivo values than aspirin. The superoxide anion plays an important role in the formation of further free radicals. It leads to the formation of peroxyl radicals during the inititation step of lipid peroxidation and also leads to the generation of hydroxyl radicals, where transition metals like iron, is a key factor. Diphenhydramine at lower concentrations, and the newly discovered histamine Hj antagonists, clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. Although the compounds did not have meaningful effects in the FRAY and ORAC assay, their significant ability to reduce lipid peroxidation and superoxide levels make them promising tools to attenuate oxidative damage. This study demonstrates the potential of these agents to be neuroprotective with a dual therpeutic effect by exerting a scavenging effect on superoxide anions and increasing dopamine levels.
Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2005.

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Egunlusi, Ayodeji Olatunde. "Novel norbornane derivatives as potential neuroprotective agents." University of Western Cape, 2020. http://hdl.handle.net/11394/7339.

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Philosophiae Doctor - PhD
Neurodegenerative disorders are characterised by progressive loss of the brain’s physiological functions as a result of gradual degeneration of neurons in the central nervous system. Even though they are classified as diseases of the elderly, occurrence earlier in life is possible, but that would suggest the influence of genetic and/or environmental factors. Due to the continuous rise in modernisation and industrialisation over the years, there has been an increase in incidence and prevalence of neurodegenerative disorders. With the advances in technology and life expectancy, the rates of the common forms (Alzheimer’s disease and Parkinson’s disease), are expected to increase exponentially by 2050. Unfortunately, there is still no clinically approved treatment or therapy to slow down or halt the degenerative process as most registered drugs only offer symptomatic relief. Confounding this issue is the lack of definite mechanism of neurodegeneration, which is still poorly defined and not completely understood. Nonetheless, the pathology of most neurodegenerative disorders is believed to be a combination of interrelated processes that eventually leads to neuronal cell death. Among the postulated processes, the impact of excitotoxicity mediated by NMDA receptor over-activation is prominent and it is implicated in virtually all neurodegenerative disorders. With this basic insight, it is believed that molecules capable of inhibiting NMDA receptors and associated calcium channels, without affecting the normal physiological functions of the brain, could potentially serve as good neuroprotective drugs. Competitive and uncompetitive blockers (MK-801 and ketamine) have been explored, but none were clinically accepted due to undesirable side effects such as hallucinations, sedation and depression. However, NGP1-01, a polycyclic cage molecule, has been shown to be neuroprotective through modulation of NMDA receptors and voltage gated calcium channels and attenuation of MPP+ -induced toxicity. A similar approach could be useful in the design and development of new neuroprotective drugs. The aim of this study was to synthesise a series of open and rearranged cage-like molecules and explore their neuroprotective potential in neuroblastoma SH-SY5Y cells. The proposed structures, with norbornane scaffolds that contained different moieties, were designed to structurally resemble NGP1-01 and MK-801. Once synthesised, the compounds were purified and characterised, and were evaluated for their biological activities. Compounds were first screened for cytotoxicity at different concentrations. Thereafter, they were evaluated for neuroprotective effects against MPP+ -induced excitotoxicity and for calcium flux modulatory effects on NMDA receptor and voltage gated calcium channels. The norbornane derivatives were synthesised and characterised, and all final products were afforded in sufficient yields. All compounds with the exception of two compounds displayed good cytotoxic profiles towards the SH-SY5Y neuroblastoma cells at 10 µM, 50 µM and 100 µM concentrations as they demonstrated percentage cell viabilities close to 100% (control treated cells). Only two compounds showed percentage cell viability of 51% and 59% at 100 µM. Utilising the same cell line, all compounds, tested at 10 µM, attenuated MPP+ -induced toxicity after 24 hours of exposure to a neurotoxin. This was evident in the 23% to 53% enhancement (significant with p < 0.05) in cell viability when compared to the MPP+ only treated cells. In comparison to known NMDA receptor and/or voltage gated calcium channel blockers (MK-801, NGP1-01 or nimodipine), the synthesised compounds demonstrated mono or dual inhibition of calcium channels as they effectively attenuated calcium influx by blocking NMDA receptors and/or voltage gated calcium channels expressed in neuroblastoma SHSY5Y cells. This group of compounds were found to be more potent NMDA receptor inhibitors, probably due to similarities with MK-801 and memantine, than voltage gated calcium channel inhibitors. All compounds demonstrated moderate to good calcium inhibitory effects at NMDA receptors in the range of 23% to 70% while a selected few displayed very little or no activity at the voltage gated calcium channels. In conclusion, 27 compounds with norbornane scaffolds were successfully synthesised and evaluated for cytotoxicity and neuroprotection. The abilities of the synthesised compounds to protect neurons from the neurotoxin MPP+ and reduce calcium flux into neuronal cells were successfully demonstrated. These characteristics are essential in neuroprotection as they may prove significant in halting or slowing down the disease progression. The compounds showing a good cytotoxicity profile, neuroprotective effects and ability to reduce calcium overload, could potentially act as neuroprotective agents with good safety profiles or contribute as lead structures to the development and design of structurally related molecules that could clinically benefit people with neurodegenerative disorders.

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Kadernani, Yakub Esmail Y. E. "Novel adamantane derivatives as multifunctional neuroprotective agents." University of the Western Cape, 2013. http://hdl.handle.net/11394/4256.

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>Magister Scientiae - MSc
The pathology of neurodegenerative disorders involves multiple steps, and it is probably for this reason that targeting one particular step in a multi-step process has only yielded limited results. Nitric oxide (NO) is synthesised from L-Arginine by an enzyme known as nitric oxide synthase (NOS). Three isoforms of NOS exist, including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). In the central nervous system (CNS), nNOS is involved in the synthesis of NO, which is involved in various neurological functions. NO is a free radical and this probably explains why an excess amount of it has been implicated in the development of neurodegenerative disorders. In the CNS, the Nmethyl- D-aspartate (NMDA) receptor in its active state allows the influx of calcium ions which activate nNOS thus increasing the amount of NO and other detrimental reactive nitrogen species within neuronal cells. Calcium entry through voltage-gated calcium channels (VGCC) may also contribute to this. Although calcium ions are important for physiological functioning, an excess is responsible for excitotoxicity, which can ultimately lead to neurodegeneration. Our aim was to synthesise a series of adamantane-derived compounds that act at multiple target sites in the neurodegenerative pathway. By conjugating benzyl and phenylethyl moieties with different functional groups (-H, -NO2, -NH2, -NHC(NH)NH2, -OCH3) to the amantadine structure, we aimed to synthesise compounds that display calcium channel and NMDA receptor (NMDAR) channel inhibition, as well as selective inhibition of nNOS. A series of compounds (-H, -NO2, -NH2, -OCH3) were obtained in yields that varied between 16.5 % and 90.25 %. These novel compounds were tested for calcium influx through VGCC and NMDAR inhibition using synaptoneurosomes isolated from rat brain homogenate against the reference compounds MK-801, NGP1-01, amantadine, memantine and nimodipine. A lack of success with the synthesis of the guanidine compounds prevented the use of the oxyhemoglobin capture assay for the determination of nNOS inhibitory activity of these compounds. The novel synthesised compounds display inhibitory activity towards VGCC and the NMDAR in the micromolar range. Further tests are recommended on compounds SE-1, SE-4, SE-11 and SE-12 as they displayed good inhibitory activity against both NMDAR- as well as ii KCl-mediated calcium influx. These novel compounds may be better therapeutic options than amantadine and memantine as they inhibit both NMDAR and VGCC-mediated calcium influx, whereas amantadine and memantine only inhibit NMDA-mediated calcium influx. These novel adamantane derived compounds may possibly serve as novel leads or potential therapeutic agents for the treatment of neurodegenerative disorders.

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Zindo, Frank T. "Polycyclic propargylamine derivatives as multifunctional neuroprotective agents." University of the Western Cape, 2018. http://hdl.handle.net/11394/6748.

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Philosophiae Doctor - PhD
The abnormal death of neurons in the central nervous system of individuals suffering from neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, takes place by an intrinsic cell suicide programme known as apoptosis. This process is triggered by several stimuli, and consists of numerous pathways and cascades which lead to the death of neuronal cells. It is this multifactorial nature of neurodegenerative diseases that has over the years seen many researchers develop compounds that may serve as multi-target directed ligands (MTDLs) which could potentially confer neuroprotection by acting simultaneously on different receptors and target sites implicated in neurodegeneration. This study was aimed at developing MTDLs that may serve as neuroprotective agents by simultaneously (a) inhibiting N-methyl D-aspartate receptors (NMDAR) and blocking L-type voltage gated calcium channels (VGCC) thus regulating the Ca2+ influx mediated excitotoxic process; (b) inhibiting the monoamine oxidase enzymes A and -B (MAO-A/B) thus allowing increase in dopamine levels in the central nervous system and reducing the levels of the highly oxidative products produced by the activity of these enzymes; (c) possessing anti-apoptotic activity to halt the neuronal cell death process. In designing the compounds we focused on the structures of rasagiline and selegiline, two well-known MAO-B inhibitors and proposed neuroprotective agents, and of NGP1-01, a known VGCC blocker and NMDAR antagonist. The first series of compounds (reported in research article 1, Chapter 3), comprised polycyclic propargylamine and acetylene derivatives. Compounds 12, 15 and 16 from this series showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18 % to 59 % in micromolar concentrations, and compared favourably to the reference compounds. In the MAO-B assay, compound 10 exhibited weak MAO-B inhibition of 73.32 % at 300 μM. The rest of the series showed little to no activity on these target sites, despite showing significant anti-apoptotic activity. This suggested the compounds in this series to be exhibiting their neuroprotective action through some other mechanism(s) unexplored in this study.

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Saathoff, John. "Curcumin/Melatonin Hybrids as Neuroprotective Agents for Alzheimer's disease." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4586.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting ~5.2 million Americans. Current FDA approved medications provide mainly symptomatic relief and there are no agents available to delay or cure this disease. Multiple factors such as amyloid-β aggregates, dyshomeostasis of biometals, oxidative stress, and neuroinflammation have been implicated in the development of AD. Even though significant advances have been made in understanding the mechanisms leading to AD, the exact etiology still remains elusive. Given AD’s multifactorial nature, a multifunctional strategy of small molecule design would help to identify novel chemical templates. Recently our lab has developed hybrid molecules of curcumin and melatonin that exhibited potent neuroprotective ability in various AD models. Further modifications identified a lead compound with potent neuroprotective and antioxidative activity in MC65 cells, while also establishing the hybrid strategy as a viable approach in providing unique chemotypes with novel pharmacology. Further preliminary biological studies suggest that the lead is orally available and exhibits multifunctional properties both in vitro and in vivo on AD pathologies, thus strongly encouraging further structural examination. Herein, we report the structural exploration of this chemical template through structure-activity relationship studies at three domains: the phenyl domain, α,β-unsaturated β-ketone amide domain, and the indole domain. Collectively, the results show that the chemical space around the curcumin portion doesn’t favor electronic or steric/hydrophobic interactions, but might favor pi-pi (π-π) and hydrogen-bond interactions. Additionally, the α,β-unsaturated β-ketone amide domain is not as important as the linearity of the β-ketone acetamide. Moreover, the results indicate that a free rotatable β-OH might be the actual moiety that is important for the observed biological activity through favorable hydrogen bonds. Finally, steric interactions are not favored in the chemical space surrounding the indole nitrogen, suggesting that hydrogen bond interactions are required for the observed neuroprotective activity. Conversely, a hydrogen bond acceptor is necessary at the 5-position of the indole ring and bulky substitutions can be accommodated, with restrictions, suggesting steric tolerance and hydrophobic interactions at this position. These modifications have yielded a series of novel compounds that are capable of modifying AD pathology while shedding further light onto the chemical scaffold thus warranting future investigations into the development, optimization, and characterization of these curcumin/melatonin hybrids as potential treatments for AD.

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Hobbs, Catherine E., and n/a. "Perinatal hypoxia-ischaemia : neuroprotective strategies." University of Otago. Department of Anatomy & Structural Biology, 2005. http://adt.otago.ac.nz./public/adt-NZDU20070221.145910.

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Perinatal hypoxia-ischaemia is a major cause of disability, including cerebral palsy, yet a neuroprotectant which fully protects the brain remains elusive. Following a hypoxic-ischaemic insult, striatal medium-spiny neurons and hippocampal CA1 neurons are vulnerable to a complex cascade of neurotoxic events. This cascade includes energy failure, a massive release of glutamate, the formation of free radicals and caspase activation. The overall aim of this thesis was to assess the efficacy of three potential neuroprotective strategies that target this cascade from different directions. Short-term, and where appropriate, long-term, neuroprotection was investigated. The first treatment strategy aimed to suppress the generation of free radicals through treatment with the potent free radical spin trap, N-tertbutyl-(2-sulphophenyl)-nitrone (S-PBN). The second compound tested was the caspase-3 inhibitor, minocycline. Finally, the third treatment strategy combined a series of S-PBN injections with 6 hours of moderate hypothermia immediately after hypoxia-ischaemia. Hypothermia is suggested to slow the rate of the neurotoxic cascade, thus potentially allowing other neuroprotective agents greater efficacy. Using an adaptation of the Rice et al. (1981) model, hypoxia-ischaemia was induced on postnatal day (PN) 8 in the right cerebral hemisphere. For the short-term studies, the rats were perfused at 14 days-of-age. The brains were dissected out and embedded in Technovit. Forty [mu]m serial sections were cut through the right striatum and hippocampus. The total number of medium-spiny neurons in the striatum and where appropriate, the total number of neurons in the hippocampal CA1 pyramidal layer, were stereologically determined using the optical disector/Cavalieri method. For the long-term study, fine motor control was assessed in half of the animals through the staircase test from 9-11 weeks-of-age. Neuroprotection was assessed in the remaining animals. All animals were sacrificed at 12 weeks-of-age. The total number of striatal medium-spiny neurons was stereologically determined in the non-behavioural animals as described above. A series of seven injections of S-PBN (100mg/kg) did not offer statistically significant neuroprotection to the striatum at one week after perinatal hypoxia-ischaemia. Similarly, a single injection of minocycline (45mg/kg) immediately after the insult did not offer significant neuroprotection to the striatum nor the CA1 region of the hippocampus at this early time-point. In contrast, when the series of S-PBN injections was combined with 6 hours of moderate hypothermia post-hypoxia-ischaemia, sterelogical analysis revealed significant neuroprotection of the striatal medium-spiny neurons to normal levels at one week after the injury. No significant neuroprotection was seen in the CA1 region of the same animals. To assess whether this impressive striatal neuroprotection was long-lasting and whether it represented functional rescue, the final experiment in this thesis investigated rat pups at 12 weeks-of-age after exposure to hypoxia-ischaemia at PN8. Treatment with S-PBN/hypothermia offered persistent neuroprotection of striatal medium-spiny neurons and preservation of fine motor skills compared to diluent-normothermia-treated controls. The long-term behavioural outcomes were compared with normal, uninjured controls and the total number of medium-spiny neurons was compared with normal numbers from the literature. These comparisons revealed that the histological and functional integrity of the striatum was rescued to normal levels. This is the first study to identify a treatment strategy that offers complete and long-lasting preservation of striatal neuronal numbers, by accurate and unbiased stereological methods, paired with persistent preservation of fine motor control following perinatal hypoxia-ischaemia.

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Singer, Cherie A. "Neurotrophic and neuroprotective effects of estrogen /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6301.

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Musakwa, Lovetone. "Chalcone and curcumin hybrids of indole propargylamines as multifunctional neuroprotective agents." University of the Western Cape, 2020. http://hdl.handle.net/11394/7959.

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Magister Pharmaceuticae - MPharm
Neurodegenerative disorders (NDs) are a range of chronic brain disorders that includes amongst others motor function loss. Parkinson’s disease (PD) is one of the common NDs that has an insidious onset and diagnosed when dopaminergic neurons in the substantia nigra are already lost. The loss creates a deficiency of the dopamine (neurotransmitter) thereby causing neurochemical imbalance resulting in the signs and symptoms of PD. NDs overlap at multiple levels so some of the symptoms overlap as well. NDs currently have no cure yet and current drug therapies only improve the quality of life of the patients by targeting the symptoms mainly. Treatment of PD currently involves different classes of drugs and depending on the stages of the disease, some drugs can be only used as an adjunct therapy. Anti-oxidants and monoamine oxidase inhibitors (MAO-I) are part of the treatment options.

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Janis, Kelly Lynn. "Investigation of the efficacy of various neuroprotection agents for their potential use in the treatment of Parkinson's disease." Diss., Connect to online resource - MSU authorized users, 2008.

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Karuppagounder, Senthilkumar S. Dhanasekaran Muralikrishnan Suppiramaniam Vishnu. "Environmental toxins and dopaminergic neurotoxicity novel neuroprotective strategies /." Auburn, Ala, 2009. http://hdl.handle.net/10415/1883.

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Li, Ka Wai. "Neuroprotective roles of cefriaxone on cultured astrocytes and neuronal cells." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1277.

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Lui, Nga Ping. "Endogenous neuroprotective mechanisms in early stages of rat parkinsonism." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1251.

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Simi, Anastasia. "Molecular basis for the anti-inflammatory properties of chlomethiazole /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-621-9/.

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Ho, Yuen-shan. "Investigation of lycium barbarum as neuroprotective drug against Alzheimer's disease." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43572388.

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Woo, Tak-yunn Tiffany, and 胡德欣. "Neuroprotective strategies in a rat model of retinal detachment." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48334911.

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Retinal detachment (RD) is a leading cause of blindness and although final surgical reattachment rate has greatly improved, visual outcome in many macula-off detachments is disappointing, mainly because of photoreceptor cell death. We previously showed that both lutein and Lycium barbarum polysaccharides (LBP) are neuroprotective in a rodent model of ischemia/reperfusion injury. The objective of this study is to investigate lutein and LBP as possible pharmacological adjuncts to surgery. Lutein: Subretinal injections of 1.4% sodium hyaluronate were used to induce RD in Sprague-Dawley rats until their retinae were approximately 70% detached. Daily injections of corn oil (control group) or 0.5mg/kg lutein in corn oil (treatment group) were given intraperitoneally starting 4 hours after RD induction. Animals were euthanized 3 days and 30 days after RD and their retinae were analyzed for photoreceptor apoptosis and cell survival at the outer nuclear layer (ONL) using TUNEL staining and cell counting on retinal sections. Glial fibrillary acidic protein (GFAP) and rhodopsin (RHO) expression were evaluated with immunohistochemistry. Western blotting was done with antibodies against cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9 to delineate lutein’s mechanism of action in the apoptotic cascade. To seek a possible therapeutic time window, the same set of experiment was repeated with treatment commencing 36 hours after RD. When lutein was given 4 hours after RD, there was significantly fewer TUNELpositive cells in ONL 3 days after RD when compared with the vehicle group. Cell counting showed that there were significantly more nuclei in ONL in lutein-treated retinae by day 30. Treatment groups also showed significantly reduced GFAP immunoreactivity and preserved RHO expression. At day 3 after RD, Western blotting showed reduced expression of cleaved caspase-3 and cleaved caspase-8 in the treatment group. No difference was found for cleaved caspase-9. When lutein was given 36 hours after RD similar results were observed. Our results suggest that lutein is a potent neuroprotective agent that can salvage photoreceptors in rats with RD, with a therapeutic window of at least 36 hours. The use of lutein in patients with RD may serve as an adjunct to surgery to improve visual outcomes. LBP: The same RD model was used for the LBP experiment. Phosphate buffered solution (PBS) or LBP in PBS was given orally through a gavage at 1mg/kg and 10mg/kg concentrations. For this experiment, animals were sacrificed 7 days after RD, and only cell counting of the ONL and TUNEL staining were performed. Both sets of results did not produce statistically significant changes with the use of LBP. Our preliminary data for the effect of LBP on retinal detachment shows no significant beneficial effect.
published_or_final_version
Medicine
Master
Master of Research in Medicine

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Nogueira, Carlos Renato Alves. "AvaliaÃÃo dos efeitos anticonvulsivantes e neuroprotetores da doxiciclina em ratos adultos jovens." Universidade Federal do CearÃ, 2008. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=2767.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
A Pilocarpina Ã um agonista colinÃrgico caracterÃstico por induzir convulsÃes que evoluem para status epilÃpticus, similar Ã epilepsia do lobo temporal humana. Neste presente trabalho, nÃs avaliamos a possÃvel aÃÃo neuroprotetora da doxiciclina, uma tetraciclina de segunda geraÃÃo, nas convulsÃes induzidas pela pilocarpina em ratos Wistar machos, que receberam pilocarpina (300mg/kg i.p) presenÃa ou na ausÃncia de doxiciclina (25 Ã 100 mg/kg) administrada intraperitonealmente uma vez ao dia durante sete dias. ApÃs a injeÃÃo de pilocarpina, foram observados os sinais colinÃrgicos perifÃricos, as latÃncias de 1Â convulsÃo e de morte. Foram determinadas as concentraÃÃes de aminoÃcidos no cÃrtex temporal atravÃs de cromatografia lÃquida de alta eficiÃncia HPLC, e a atividade do sistema antioxidante, catalase e as dosagens dos nÃveis de TBARS e nitrito. Os resultados mostraram que a doxiciclina nÃo alterou os sinais colinÃrgicos perifÃricos, contudo aumentou a latÃncia decorrida para a primeira convulsÃo (1.6 a 5 vezes), quando comparada ao grupo (P300). Resultados semelhantes foram demonstrados com a latÃncia de morte, que foi aumentada de 1.9 a 9.9 vezes. Observou - se que o prÃ-tratamento com doxiciclina 50 mg/kg foi capaz de reduzir em 25% os nÃveis de MDA, 64% os nÃveis de nitrito e 67.7% a atividade da catalase no cÃrtex temporal desses animais, demonstrando com clareza seu potencial antioxidante. Interessantemente, a doxiciclina diminuiu as concentraÃÃes de glutamato de 28 a 33%, e aumentou GABA em 112 e 91%, nas dose de 50 e 100mg/kg respectivamente nos animais administrados com P300, Na maior dose, a droga alterou os nÃveis de aspartato e taurina, diminuindo em 61% aspartato enquanto elevou os nÃveis de taurina em cerca de 34%. Surpreendentemente, somente a menor dose alterou os nÃveis de glicina, aumentendo a concentraÃÃo deste aminoÃcido em 132%. Em conclusÃo, mostramos que o inÃcio e a intensidade das convulsÃes induzidas pela pilocarpina foram significativamente reduzidos pela doxiciclina. Portanto, pelo menos em parte, este mecanismo de aÃÃo parece estar relacionado a uma diminuiÃÃo nos nÃveis de aminoÃcidos excitatÃrios e a um aumento nas concentraÃÃes de aminoÃcidos inibitÃrios no cÃrtex temporal desses animais.
Pilocarpine is known to induce convulsions leading to status epilepticus, similar to the temporal lobe epilepsy in humans. In the present work, we evaluated the possible protection affored by doxycyvline, a 2nd generation tetracycline, agaist pilocarpine- induced convulsions in male Wistar rats (P300mg/kg, i.p) in the absence and in the presence of doxicycline (25 to 100 mg/kg i.p.) daily for 7 days.After the pilocarpine injection, all groups were observed for cholinergic signs, latency to the first convulsion and latency to death. Besides, amino acid concentrations in temporal cÃrtices were determined by RP-HPLC, as well catalase activity and levels of TBARS and Nitrite. Results showed that doxycycline did not alter cholinergic signs but increased the latency time to the first convulsion (1.6 to 5 times increase), as compared to P300, and the highest effect was observed with the dose of 25 mg/kg. Similar results were demonstrated to death latency that increased from 1.9 to 9.9 times with doxyciclyne at the doses of 25, 50 and 100 mg/kg. In fact we showed that the pre-treatment with doxycycline decreased in 25% MDA levels, 64% nitrite levels and 67.7% catalase activity. Interestingly, doxycycline decreased glutamate concentrations in 28 and 33% and increased GABA in 112 and 91% at the doses of 50 and 100mg/kg respectively. At the higher dose the drug altered aspartate and taurine concentrations, decreased aspartate levels in 61%, while increasing taurine levels in 34%. Surprisingly, only the lower dose altered glycine levels, increasing its concentration by 132%. In conclusion, we showed that the onset and intensity of pilocarpine-induced seizures were significantly reduced by doxycycline. Furthermore, at least in part, its mechanism of action seems to be mediated by the decrease and increase of excitatory and inhibitory aminoacids, respectively. In addiction the doxycycline capacity to reduce the oxidative stress associated with the pilocarpine-induced may also play a role

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Rees, Daniel J. "Natural and synthetic GHSR1a agonists as neuroprotective agents in models of Parkinson's disease." Thesis, Swansea University, 2017. https://cronfa.swan.ac.uk/Record/cronfa40946.

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in humans. It is characterised by the progressive loss of the A9 (Girk2+) subpopulation of dopamine (DA) neurones in the Substantia Nigra Pars Compacta (SNpc) resulting in resting tremor, bradykinesia and rigidity. The majority of PD cases are idiopathic. However, environmental toxins that inhibit the mitochondrial electron transport chain cause PD-like symptoms and recent studies of rare familial PD implicate metabolic dysfunction as a possible cause of DA nerve cell loss. We propose that the homeostatic hormone, acyl-ghrelin, may prevent DA neurone loss by preserving nerve cell metabolism during bioenergetics stress. In the in-vivo MPTP-toxin model of PD acyl-ghrelin prevents SNpc DA neurone loss in an acyl-ghrelin receptor (GHSR)-dependent manner (Andrews et al.2009). Here, using the eGFP-GHSR reporter mouse we demonstrate co-localised expression of the GHSR with TH+ and Girk2+ SNpc neurones. This suggests that acyl-ghrelin may exert a direct protective effect on A9 DA neurones via GHSR+ signalling. We show that acyl-ghrelin attenuated the 6-OHDA-induced SN lesion in unilateral lesioned rats. Moreover, this neuroprotection is consistent with the preservation of motor function. Using a mouse-midbrain-derived neuronal cell line (SN4741), immune-positive for TH+/ Girk2+/GHSR+, we assess the neuroprotective potential of acyl-ghrelin and GHSR1a agonist, JMV2894, in an in-vitro rotenone-based PD model. Furthermore, we show acyl-ghrelin as a modulator of intra-cellular AMPK and ACC phosphorylation and investigate the protective effects on mitochondrial health and morphology using automated images analysis and TEM. Acyl-ghrelin activated cellular pathways associated with protecting against energetic stress and promoting healthy aging. These data suggest that Acyl-Ghrelin may be a potential new therapeutic target for PD.

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CESCON, ELEONORA. "Reversible and covalent protein kinase CK1δ inhibitors: potential neuroprotective agents in neurodegenerative diseases." Doctoral thesis, Università degli Studi di Trieste, 2023. https://hdl.handle.net/11368/3040842.

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Besides its well-known role in controlling the circadian rhythm and cancer, protein kinase CK1δ is involved in the onset of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). This pleiotropic role of CK1δ makes it an attractive target for innovative therapeutic approaches. The aim of this PhD project is therefore to develop both CK1δ reversible and covalent inhibitors. The catalytic domain (aa. 1-296) of CK1δ was expressed and purified to obtain a pure, properly folded and enzymatically active recombinant protein for in vitro biochemical studies, to deeply characterize the kinase binding site and the interactions of our inhibitors, as well as to obtain co-crystal structures. As regards the development of ATP-competitive inhibitors, the [1,2,4]triazolo[1,5-a][1,3,5]triazine (TT) nucleus was investigated since it has already successfully demonstrated to mimic the ATP’s adenine ring in interacting with the kinase’s catalytic domain. Starting from a previous series of TT kinase inhibitors having diamine substituents at the 5 position, new triazolo-triazine 5,7-diamines were synthesized. In particular, a new sub-set of molecules in which the terminal amino group was substituted with different aromatic systems or less bulky groups to study the role of the steric hindrance in this position as any additional interactions with the catalytic pocket was designed. After chemical characterization, all the compounds were evaluated towards CK1δ through a luminescence based assay and the blood-brain barrier (BBB) permeability of the most active compounds was predicted using the PAMPA-BBB assay. Also, their cytotoxicity was investigated with the MTT assay. In parallel, covalent inhibitors of CK1δ were designed and synthesized by inserting different electrophilic moieties at the 2-position of the phenyl group of known CK1δ inhibitor scaffold. The catalytic lysine (Lys-38), was identified as the nucleophile target for the covalent bond formation. The synthesized compounds were tested on CK1δ and IC50 data revealed that the aldehyde moiety is the most suitable electrophile (IC50 = 241 nM). Several experiments were conducted to demonstrate the covalent inhibitory mechanism. Results of the assays performed to demonstrate the dependence of the inhibitory activity on time and ATP concentration suggest a mixed ATP-competitive/un-competitive behavior. TSA experiments confirmed the stabilizing effect of the ligand towards CK1δ. Furthermore, the covalent adduct formation was investigated through intact mass spectrometry experiments and first co-crystallization attempts were carried out. 1H-NMR studies allowed to assess the reactivity of the electrophilic warhead towards a lysine’s amino group surrogate. Notably, despite the presence of a polar aldehyde substituent, the covalent compound demonstrated to be able to passively permeate the BBB and the MTT assay resulted in a good cell viability showing also a potential neuroprotective action of the covalent derivative.
Besides its well-known role in controlling the circadian rhythm and cancer, protein kinase CK1δ is involved in the onset of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). This pleiotropic role of CK1δ makes it an attractive target for innovative therapeutic approaches. The aim of this PhD project is therefore to develop both CK1δ reversible and covalent inhibitors. The catalytic domain (aa. 1-296) of CK1δ was expressed and purified to obtain a pure, properly folded and enzymatically active recombinant protein for in vitro biochemical studies, to deeply characterize the kinase binding site and the interactions of our inhibitors, as well as to obtain co-crystal structures. As regards the development of ATP-competitive inhibitors, the [1,2,4]triazolo[1,5-a][1,3,5]triazine (TT) nucleus was investigated since it has already successfully demonstrated to mimic the ATP’s adenine ring in interacting with the kinase’s catalytic domain. Starting from a previous series of TT kinase inhibitors having diamine substituents at the 5 position, new triazolo-triazine 5,7-diamines were synthesized. In particular, a new sub-set of molecules in which the terminal amino group was substituted with different aromatic systems or less bulky groups to study the role of the steric hindrance in this position as any additional interactions with the catalytic pocket was designed. After chemical characterization, all the compounds were evaluated towards CK1δ through a luminescence based assay and the blood-brain barrier (BBB) permeability of the most active compounds was predicted using the PAMPA-BBB assay. Also, their cytotoxicity was investigated with the MTT assay. In parallel, covalent inhibitors of CK1δ were designed and synthesized by inserting different electrophilic moieties at the 2-position of the phenyl group of known CK1δ inhibitor scaffold. The catalytic lysine (Lys-38), was identified as the nucleophile target for the covalent bond formation. The synthesized compounds were tested on CK1δ and IC50 data revealed that the aldehyde moiety is the most suitable electrophile (IC50 = 241 nM). Several experiments were conducted to demonstrate the covalent inhibitory mechanism. Results of the assays performed to demonstrate the dependence of the inhibitory activity on time and ATP concentration suggest a mixed ATP-competitive/un-competitive behavior. TSA experiments confirmed the stabilizing effect of the ligand towards CK1δ. Furthermore, the covalent adduct formation was investigated through intact mass spectrometry experiments and first co-crystallization attempts were carried out. 1H-NMR studies allowed to assess the reactivity of the electrophilic warhead towards a lysine’s amino group surrogate. Notably, despite the presence of a polar aldehyde substituent, the covalent compound demonstrated to be able to passively permeate the BBB and the MTT assay resulted in a good cell viability showing also a potential neuroprotective action of the covalent derivative.

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20

Ho, Yuen-shan, and 何宛珊. "Investigation of lycium barbarum as neuroprotective drug against Alzheimer's disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43572388.

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21

Fernandes, Mara Yone Soares Dias. "Efeito neuroprotetor do α-bisabolol em camundongos submetidos Ã isquemia cerebral focal permanente." Universidade Federal do CearÃ, 2015. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=14886.

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FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico
O acidente vascular cerebral (AVE) Ã uma das principais causa de mortalidade no Brasil, acometendo cerca de 200.000 indivÃduos anualmente. A fisiopatologia do AVE isquÃmico envolve uma complexa cascata de eventos como a inflamaÃÃo e o estresse oxidativo que podem Ã morte neuronal e dÃficits cognitivos. O α-bisabolol Ã um Ãlcool sesquiterpeno, monocÃclico, que ocorre na natureza e Ã encontrado como constituinte majoritÃrio do Ãleo essencial sintÃtico da Matricaria chamomilla, que possui atividade antiinflamatÃria, antioxidante e anti-apoptÃtica jÃ descritas. Para avaliar o efeito neuroprotetor deste composto em camundongos submetidos Ã oclusÃo permanente da artÃria cerebral media (pMCAO), os animais foram prÃ e pÃs tratados com α-bisabolol nas doses de 50, 100 e 200 mg/kg, v.o, durante 24, 48, 72, 96 ou 120 horas apÃs a isquemia. Os animais foram avaliados 24h apÃs a isquÃmia para verificar a Ãrea de lesÃo isquÃmica, avaliaÃÃo neurolÃgica e atividade da mieloperoxidase. 72 horas apÃs a pMCAO, os testes de atividade locomotora, memÃria de trabalho e memÃria aversiva recente foram realizados. 96 horas apÃs a pMCAO foi realizado o teste do reconhecimento de objecto, e os animais foram eutanasiados para a realizaÃÃo da Imunohistoquimica para TNF-α, iNOS e GFAP e anÃlise histologica para Cresil violeta e Fluoro Jade C. Finalmente, 120h apÃs a isquemia, avaliou-se a memÃria espacial. O α-bisabolol reduziu significativamente a lesÃo isquemica e o dÃficit neurolÃgico e normalizou a atividade locomotora. O α-bisabolol mostrou proteÃÃo contra os dÃficits nas memÃrias de trabalho, espacial, reconhecimento de objeto e aversiva. O α-bisabolol (200 mg/kg) preveniu significativamente o aumento da MPO e TNF-α no cÃrtex temporal e o aumento do iNOS tanto no cÃrtex temporal como no estriado. Tambem preveniu o aumento da astrogliose nessas Ãreas. O α-bisabolol (200 mg/kg) mostrou protecÃÃo contra a morte neuronal. Os resultados do presente estudo mostraram que o α-bisabolol possui atividade neuroprotetora provavelmente devido a sua aÃÃo antiinflamatÃria, mas outros mecanismos nÃo podem ser descartados.
Stroke is the leading cause of mortality in Brazil, affecting about 200,000 individuals annually. The pathophysiology of ischemic stroke involves a complex cascade of events such as inflammation and oxidative stress which will lead to neuronal death and cognitive deficits. The α-bisabolol is a sesquiterpene alcohol, natural, monocyclic, found as main constituents of the essential oil of Matricaria chamomilla, which has anti-inflammatory, antioxidant and anti-apoptotic already described. To evaluate the neuroprotective effects of this compound in mice underwent permanent occlusion of the middle cerebral artery (pMCAO), the animals were pre and post treated with α-bisabolol at doses of 50, 100 and 200 mg / kg, orally for 24, 48, 72, 96 or 120 hours after pMCAO. The animals were evaluated 24 hours after ischemia to verify the area of ischemic damage, and neurological evaluation and myeloperoxidase activity. Seventy-two hours after pMCAO, the locomotor activity tests, working memory and aversive recent memory were performed. Ninety six hours after the pMCAO was performed the object recognition test, and the animals were euthanized for carrying out the immunohistochemistry for TNF-α, iNOS and GFAP and for histology analyes Cresil violet and Fluoro Jade C. Finally, 120 h after pMCAO, the spatial memory was evaluated. The α-bisabolol reduced significantly ischemic damage and neurological deficit and normalized the locomotor activity. The α-bisabolol showed protection against the deficits in working, spatial, object recognition and aversive memories. The α-bisabolol (200 mg / kg) significantly prevented the increase of MPO and TNF-α in the temporal cortex and the increased of iNOS both in the temporal cortex and in striatum. Also prevented the increase in astrogliosis in there area. The α-bisabolol (200 mg / kg) showed protection against neuronal death. The results of this study showed that α-bisabolol has neuroprotective activity probably due to its anti-inflammatory action, but other mechanisms can not be discarded.

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22

Rogers, Derek Charles. "The effects of neuroprotective agents on in vitro and in vivo models of neurotoxicity." Thesis, University of Hertfordshire, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283890.

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23

Ramsunder, Adrusha. "An investigation into the possible neuroprotective or neurotoxic properties of metrifonate." Thesis, Rhodes University, 2005. http://hdl.handle.net/10962/d1007560.

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Alzheimer's disease is a progressive neurodegenerative disorder, in which there is a marked decline in neurotransmitters, especially those of the cholinergic pathways. One of the approaches to the symptomatic treatment of Alzheimer's disease is the inhibition of the breakdown of the neurotransmitter acetylcholine, using an acetylcholinesterase inhibitor. One such drug tested, is the organophosphate, metrifonate. Any drug used for the treatment of neurodegenerative disorders should preferably not induce further neurological damage. Thus, in the present study, we investigated whether or not metrifonate is neuroprotective. The in vivo and in vitro effect of this drug on free radicals generation shows that metrifonate increases the level ofthese reactive species. Lipid peroxidation induced using quinolinic acid (QA) and iron (II) and show that metrifonate increased the peroxidative damage induced by using quinolinic acid. Metrifonate is also able to induce lipid peroxidation both in vivo and in vitro. This was reduced in vitro in the presence of melatonin. Using iron (II), in vi/ro, there was no significant difference in the level of lipid peroxidation in the presence of this drug. An investigation of the activity of the mitochondrial electron transport chain and complex I of the electron transport chain in the presence of metrifonate revealed that metrifonate reduces the activity of the electron transport chain at the level of complex I. The activity of the mitochondrial electron transport chain was restored in the presence of melatonin. Pineal organ culture showed that metrifonate does not increase melatonin production. Histological and apoptosis studies show that tissue necrosis and apoptosis respectively, occur in the presence of this agent, which is reduced in the presence of melatonin. Metal binding studies were performed USing ultraviolet spectroscopy, and electrochemical analysis to examine the interaction of metrifonate with iron (II) and iron (III). No shift in the peak was observed in the ultraviolet spectrum when iron (ll) was added to metrifonate. Electrochemical studies show that there may be a very weak or no ligand formed between the metal and drug. This study shows that while drugs such as metrifonate may be beneficial in restoring cognitive function in Alzheimer's disease, it could also have the potential to enhance neurodegeneration, thus worsening the condition, in the long term.
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Rizzi, Caterina. "NGF steers microglia toward a neuroprotective phenotype." Doctoral thesis, Scuola Normale Superiore, 2019. http://hdl.handle.net/11384/85996.

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Microglia are the resident immune cells of the Central Nervous System (CNS). Beside classic in ammatory activities shared with macrophages, microglia actively participate in activity-dependent plasticity and learning processes [1] [2], as sculpting the neuronal circuitry during development [3] [4]. Microglia have been shown to be key players in the pathogenesis and progression of many neurodegenerative disorders and they are responsible for brain homeostasis and monitor the brain environment with their ever-moving processes [5] [6]. However, their role, either promoting or preventing pathology, is debated. On one hand, excessive activation of microglia leads to oxidative stress, neuroinammation, and eventually neuronal death [7]. On the other hand, microglial activation might be harnessed to carry out protective activities in the brain, such as phagocytosis of aggregates, synaptic pruning and formation, and the maintenance of healthy neuronal circuits [8]. Therefore, it is important to identify and modulate selectively the neuroprotective activities of microglia. The idea of microglia cells as the natural scavengers of the brain becomes especially interesting when dealing with diseases with the loss of proteostasis such as Alzheimer's disease. In the search of neuroprotective agents against neurodegeneration, neurotrophins have been historically considered as potential therapeutic candidates but usually with actions targeted to natural neuronal population. In this thesis I tested the hypothesis that microglia represent a new target cell for Nerve Growth Factor (NGF) in the brain. So far sparse experiments in the literature suggest this insight. In the literature microglia cells are known to be a source of neurotrophins [9] [10][11], most notably the Brain Derived Neurotrophic Factor (BDNF) which has been shown to promote synapse formation [1] and NGF [12] [13]. However, the extent of the modulation NGF might exert on physiological microglial functions and how this effect might come into play in neurodegenerative disorders has not been in- vestigated yet. Indeed, the main cellular targets of the neurotrophin Nerve Growth Factor (NGF) [14] in the central nervous system are considered to be the cholinergic neurons of the basal forebrain (BFCNs) [15], while its sources are mainly cortical and hippocampal neurons [16]. Consistently, interference with NGF signaling (trkA-NGF signalling) in the adult brain leads to de cits of the cholinergic system that has been related to the mechanisms driving neurodegeneration, as in the AD11 transgenic mouse model [17] [18]. The expression of anti-NGF antibodies selectively neutralizing mature NGF in the adult brain determines a progressive comprehensive neurodegeneration with neuroinflammation as the earliest observed change, at a presymptomatic phase [19] [20]. A similar progressive neurodegeneration is observed in trans- genic mice expressing a neutralizing anti TrkA antibody in the adult brain [21]. Changes in NGF homeostasis in the brain, with particular regard to the ratio of NGF to proNGF levels, have also been linked to Alzheimer's disease [22]. However the overall neurodegenerative picture induced by anti- NGF or anti-TrkA antibodies in those transgenic models is much broader than what one would expect on the basis of an action of the antibodies on the BFCNs exclusively. Moreover, the loss of NGF-TrkA signaling in the CNS, obtained by conditionally deleting NGF or TrkA genes in CNS cells derived from nestin-positive cells, has proven not to be sufficient in inducing severe cognitive impairments or neurodegen- eration in mice [23]. Altogether, this body of results has motivated our search for non neuronal targets of NGF in the adult brain. Microglia was a strong candidate, because (1) previous work had suggested that NGF could modulate some aspects of microglial cells in culture [12] and (2) transcriptomic studies in the AD11 mouse model expressing anti-NGF had shown that neuroinammation is the earliest phenotypic alteration, already at a presymptomatic phase (1 month of age; [19] [20]). In this thesis I show that microglia cells are true target of NGF both in vivo and in vitro and that the activity carried out by this neurotrophin on these myeloid cells might result neuroprotective in the context of Alzheimer's Disease.

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25

Li, Hongying, and 李洪英. "Secondary degeneration after partial optic nerve transection : mechanisms and the neuroprotective effects of lycium barbarum." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/197129.

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Glaucoma is a neurodegenerative disease and one of the major causes of blindness in the world. Secondary degeneration is involved in glaucoma. The retinal ganglion cells (RGCs) which are vulnerable to secondary degeneration in glaucoma are the promising target population for therapeutic intervention. Partial optic nerve transection (PONT) model has been established in the last decade. Primary and secondary degeneration can be separated in different regions of retinas in this model. Therefore, PONT is a good model for the study of mechanisms of secondary degeneration and the drug screening for secondary degeneration. Lycium barbarum (L. barbarum) has been shown to be neuroprotective for cortical neurons in vitro. It has also been shown that L. barbarum could delay RGCs death in a rat ocular hypertension model. In order to further investigate the effects of L. barbarum for RGCs, two models, complete optic nerve transaction (CONT) model and PONT model, were employed in my study. My results showed that the polysaccharide extract from L. barbarum (LBP) could partly prevent RGCs from death in the inferior retinas 4 weeks after PONT whereas it could not reduce the loss of RGCs after CONT. The1,1'-dioctadecyl-3, 3, 3’, 3’-tetramethylindocarbocyanine perchlorate(DiI) labeling of RGCs whose axons were transected showed that the majority of labeled cell bodies existed in the superior retinas. The result meant that more cell bodies in the superior retinas would die from primary degeneration than in the inferior retina after PONT. Therefore my results indicated that LBP protected RGCs which would die from secondary degeneration rather than primary degeneration. The results of Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining showed that RGCs underwent apoptosis 1 week after PONT. Western-blot analysis demonstrated that oxidative stress was involved in the degeneration of RGCs after PONT. Furthermore, c-Jun N-terminal kinases (JNKs) pathway was activated which was indicated by an increase ofphospho-JNK2/3(p-JNK2/3)and phospho-c-jun(p-c-jun). Our results also revealed that orally feeding of LBP could increase the expression of manganese superoxide dismutase (MnSOD) and insulin growth factor-1 (IGF-1)and decrease the expression of p-JNK2/3 and p-c-jun. The results from optic nerve (ON) study showed that glial cells, including astrocytes and microglias/macrophages, were activated after PONT. Oxidative stress and inflammation were involved in the process. Secondary degeneration of ON was not obvious and LBP exerted no protective effects on the survival of axons in the ON. The multifocal electroretinography (mfERG) study showed that both the functions of inner retinas and outer retinas were damaged after PONT. The results indicated that other cell types or the synapses between different cell types were damaged in addition to RGCs. LBP could improve the function of the whole retinas, including both inner retinas and outer retinas after PONT. In conclusion, our results indicated that LBP protected RGCs from secondary degeneration via inhibiting oxidative stress and the activation of JNK pathway.LBP could also improve the function of both inner retinas and outer retinas after PONT.
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Anatomy
Doctoral
Doctor of Philosophy

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26

Bienemann, Alison Sarah. "Assessing viral vectors as gene therapy agents and the study of neuroprotective effects of HSP70." Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492644.

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The experiments outlined in this thesis were designed to: (i) evaluate the utility of Equine infectious anaemia lentiviral (EIAV) vectors as gene therapy agents in the CNS; (ii) investigate the function and neuroprotective role of Hsp70 and Hsp40.

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27

Elabi, Osama. "The effect of L-dopa and neuroprotective agents on cell replacement therapy for Parkinson's disease." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/103900/.

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Parkinson disease (PD) is the second most common neurodegenerative disease affecting 1.8% of population aged over 65 years. The current medications that control the symptoms of the disease are associated with limited efficacy and induction of side effects (dyskinesia) at later stages of the disease. One promising future therapy in PD is cell replacement therapy, however clinical trials declared inconsistent outcomes and developing dyskinesia related to the graft. Studies later suggested suboptimal conditions contributed on these outcomes. This thesis builds on this knowledge endeavouring to support cell transplantian therapy in Parkinson disease in models that are more closely aligned to the clinic thorough considering anti-parkinsonian medications in the model. It is addressed the low survival and efficacy problem of the transplanted cells examining neuroprotective agents that have previously shown the ability to protect nigrostriatal dopaminergic neurons against toxic challenges. In addition, this thesis characterises stem cell transplantation, the potential cell source for transplantation that can overcome the many practical and ethical issues surrounding foetal tissue. In the first part of the thesis, the investigations on finding neuroprotective agents to support graft survival and efficacy was achieved in the unilateral 6-OHDA lesioned rat model, treated with chronic L-dopa, (the gold standard anti- Parkinson medication), prior to, and following, cell transplantation. The results revealed for the first time that Glucagon Like Peptide-1 (GLP- 1) receptor agonists (exendin-4 and liraglutide) were capable of improving graft size and the motor and behaviour recovery results from peripheral administration. Importantly, this protection was affected by the presence or absence of L-dopa treatment, as exendin-4 supported the graft only in absence of L-dopa while liraglutide supported the graft only in the presence of L-dopa. While other neuroprotective agents (ghrelin and ghrelin receptor agonist) failed to support graft survival or efficacy in the same animal model. In the second part of the thesis, the characterisation of different source of stem cells derived dopaminergic neurons revealed for the first time that these cells can survive and function in the striatum of 6-OHDA rat model primed with chronic L-dopa treatment and exposed to L-dopa treatment for 16 weeks after transplantation. I show, for the first time, that these cells are capable of ameliorating L-dopa induced dyskinesia.

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28

Lau, Yuk-fan Silvania, and 劉玉芬. "The neuroprotective effect of lycium barbarum polysaccharides on retinal neurons in a novel acute glaucoma attack animal model." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47309325.

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Acute glaucoma is an ocular emergency and sight -threatening disease which is caused by a sudden increase in intraocular ocular pressure (IOP) due to blockage of aqueous humor outflow. Acute glaucoma can result in permanent loss of visual acuity and visual field (VF). Prophylactic or therapeutic medicine is rare for acute glaucoma. In animal studies, a well-established model to investigate this acute IOP spike is by fluid infusion and adjustment of the fluid level to induce high IOP within a few seconds. However, there is no blockage of aqueous outflow and the increase in intraocular pressure is unrealistically rapid. To mimic the IOP profile in human acute glaucoma attack, we propose the use of an ophthalmic viscosurgical device (OVD), Healon 5 (AMO, Santa Ana, CA, USA) which is injected intracamerally to block aqueous outflow. The IOP is allowed to increase naturally inside the globe. We found that Healon 5 can induce an acute elevation in IOP with very similar characteristics to those observed in humans. For example, the IOP profile during the attack, changes in the anterior segment and retinal nerve fibre layer (RNFL) thinning are all consistent with findings in human acute angle closure glaucoma (AACG). We believed that our new model can more accurately reflect acute glaucoma than other animal models. Based on these findings we further tested the neuroprotective effect of Lycium barbarum polysaccharides (LBP) on retinal neurons against an acute rise in IOP (attack) with the new model. L. barbarum is an herb that has been used in Chinese medicine for thousands of years. The fruit of this plant is believed to be good for the health of the eyes. In our study we found that oral administration of LBP preceding an acute glaucoma attack can preserve the visual function of the animals despite the loss of neurons in the retinal ganglion cell layer (RGCL). L. barbarum intake seems to inhibit secondary cell death and progression of the disease. In conclusion, we had successfully established a new acute glaucoma attack animal model by intracameral injection of Healon 5. This model more closely resembles the condition observed in human acute glaucoma. We also found that LBP has a prophylactic neuroprotective effect against an acute glaucoma attack in animals. It can protect the visual function and possibly inhibit secondary cell death. Oral consumption of LBP as a health supplement may provide extra benefit to people who are at high risk of developing acute glaucoma, in addition to the protective effects of LBP against other diseases.
published_or_final_version
Anatomy
Master
Master of Philosophy

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29

Xiu, Jin. "Distribution and function of nicotinic acetylcholine receptors in glia cells and neurons with focus on the neuroprotective mechanisms of cholesterol-lowering drugs in Alzheimer's disease /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-758-8/.

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30

Palvie, Stefanie Michelle. "An investigation into the neuroprotective effects of dehydroepiandrosterone." Thesis, Rhodes University, 2006. http://hdl.handle.net/10962/d1003260.

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Dehydroepiandrosterone, a C-19 steroid, is found endogenously with the highest circulating serum levels. It is converted to important steroids such as the sex hormones oestrogen and testosterone. DHEA has come under the spotlight as a purported “fountain of youth” due to its well-characterised age-related decline. The supplementation of DHEA in both the elderly and those with a pathophysiological deficiency has been shown to be of benefit, particularly with regard to wellbeing and depression. The role of DHEA in the periphery has not been elucidated beyond its role as a precursor hormone in sex steroid biosynthesis, though it has been established as a neuroactive neurosteroid, capable of exerting neuroprotective effects in the brain. Since the importance of free radicals in aging and neurodegeneration is well established, investigations were conducted on the ability of DHEA to inhibit free radical generation or scavenge existing free radicals. DHEA was able to significantly inhibit quinolinic acid-induced lipid peroxidation, a measure of membrane damage, over a range of concentrations, although the reduction did not appear to be dose-dependent. This was observed in both in vitro and in vivo studies. Thus, the ability of a compound to reduce the degree of lipid peroxidation may indicate its value as a neuroprotectant. However, DHEA did not significantly reduce cyanide induced generation of the superoxide free radical, suggesting that DHEA is not an effective free radical scavenger of the superoxide anion and that the reduction in lipid peroxidation does not occur through a scavenging mechanism. Apoptosis is a physiological process which is necessary for development and homeostasis. However, this form of programmed cell death can be initiated through various mechanisms and too much apoptotic cell death results in deleterious effects in the body. DHEA was shown not to induce apoptosis. Even the lowest concentration of DHEA investigated in this thesis shows a remarkable decrease in the degree of apoptosis caused by intrahippocampal chemical insult by the neurotoxin quinolinic acid. Cresyl violet was used to visualise tissue for histological examination which revealed that DHEA is able to preserve the normal healthy morphology of hippocampal cells which have been exposed to quinolinic acid. Cells maintained their integrity and showed little evidence of swelling associated with necrosis. Organ culture studies were performed by assessing the impact of DHEA on several pineal metabolites. The study revealed that DHEA exerted an effect on the metabolism of indoleamines in the pineal gland. Melatonin, the chief pineal hormone, did not appear to be affected while the concentrations of N-acetylserotonin, serotonin and methoxytryptamine showed significant alterations. Thus, the neuroprotective mechanism of DHEA does not appear to be mediated by an increase in the presence of melatonin. The biological importance of metal ions in neurodegeneration is also well established and thus the potential interaction between DHEA and metal ions was considered as a mechanism of action. Spectroscopic and electrochemical analyses were performed to determine whether DHEA is able to interact with metal ions as a ligand. These reveal that DHEA does not form a strong bond with the metals investigated, namely copper (II) and iron (III), but that a weak interaction is evident. These investigations were conducted in a rodent model, which has neither large amounts of endogenous DHEA, nor the enzymatic infrastructure present in humans. Thus, the theory that DHEA exerts its effects through downstream metabolic products is unlikely. However, these investigations reveal that there is merit in the statement that DHEA itself is a neuroprotective molecule, and confirm that the further investigation of DHEA is an advisable strategy in the war against neurodegeneration and aging.

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31

Wong, Kai-hei Harmony, and 黃啟希. "Neuroprotective effects of lycium barbarum polysaccharide on corticosterone-induced damage on retinal ganglion cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48395110.

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It has been known that light input can affect the emotions of a person. The depressive syndrome Seasonal Affective Disorder (SAD) is an effective example of the power of light in changing the mood of a person. Patients with SAD have recurring depressive episodes that follow seasonal changes, which is due to the changing daylight hours. This phenomenon suggests that there would be receptors in the retina that would not simply be responsible for vision, but also for the regulation of non-visual signals such as emotion. In many animals, projections have been found from the retina to the dorsal raphe nucleus (DRN). This brain region is a serotonergic area and has been found to be involved in the occurrence of depression. As such, the cells in the retina which were found to have projections to the DRN have a high possibility to be involved in emotion regulation. Retinal Ganglion Cells (RGCs) are classified into many types. A specific type known as an alpha cell is suspected to be the DRN-projecting subtype. This study uses Lycium Barbarum Polysaccharide (LBP) as a treatment in protecting the large RGCs from corticosterone (CORT) -induced damage. The aim is to observe if LBP will provide neuroprotection to large sized RGCs damaged by 40mg/kg or 50mg/kg CORT, and hence if LBP can be further investigated as a possible anti-depressant drug. This study observed that although LBP did not reduce large cell deaths, it reduced cell atrophy of the RGCs under high dosage of CORT (50mg/kg). For the same number of cells counted, treatment groups with a high dose CORT injection found more cells over 300μm2 in area than cells under 300μm2. Also, it was found that the temporal quadrants were more sensitive to cell size change than the nasal quadrants, paving way for more in-depth research of the spatial sensitivity to CORT or to LBP. The findings in this study indicate that LBP does indeed have a neuroprotective effect on large RGCs, although this effect is limited and as of yet seems conditional, as this study ignores the effect of CORT and LBP on other large cell properties such as the dendritic field size and the amount of synapses. Further studies are needed to determine the mechanism of the neuroprotective effect of LBP and to determine the exact site of action LBP works on.
published_or_final_version
Anatomy
Master
Master of Medical Sciences

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Syers, Jacqueline Ann. "An evaluation of potential neuroprotective strategies in rats with partial MPP+ or 6-OHDA lesions of the substantia nigra." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265250.

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Yang, Di, and 楊荻. "Neuroprotective effects of lycium barbarum extracts in cerebral and retinal ischemia/reperfusion injury." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206738.

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Ischemic stroke is a devastating cerebrovascular disease resulting in high mortality rate and distressing sequelae such as hemiplegia, ataxia and even visual impairment. Retinal ischemia refers to a common pathological feature shared by many blinding diseases including retinal vascular occlusions, diabetic retinopathy, glaucoma, and retinopathy of prematurity. Ischemia/reperfusion injury is implicated in both of these pathological conditions, which greatly impact on one’s daily life. The eventual consequence of the insult is irreversible neuronal cell death and functional deterioration. Apart from current symptomatic treatment for these diseases, researchers and clinicians are dedicated to look for ideal neuroprotectant to meet the clinical needs. Traditional Chinese medicine has been received accumulating attention in recent years, and Lycium barbarum is one of them. The polysaccharides (LBP) utilized in the present study are the rich extracts of the fruit of Lycium barbarum that has been shown to exert many biological effects. This study aims to evaluate its protective effects in cerebral and retinal ischemia, which has not yet been fully investigated. A well-established rodent model, middle cerebral artery occlusion, was utilized in the present study to mimic cerebral and retinal ischemia/reperfusion injury. In the study of cerebral ischemia, both pre-treatment and post-treatment of LBP were explored. Seven-day LBP pre-treatment revealed significant protection against neurological deficits and cerebral infarction. Besides, it attenuated cerebral edema and glial activation, as well as preserved blood-brain barrier integrity. Further study showed that these beneficial effects of LBP pre-treatment might act via anti-apoptosis, antioxidation and anti-inflammation. However, similar findings were not noted in LBP post-treatment experiments, possibly due to the timing of intervention. In the investigation of retinal ischemia, the observation time was prolonged to 7 days after the insult. Electroretinogram was used to evaluate the functional alternation of retinal neurons. Sustained retinal dysfunction was induced by two-hour ischemia. LBP pre-treatment with continuous daily supplementation effectively alleviated visual dysfunction and protected the retina from morphological impairment including neuronal death, glial activation and blood-retinal barrier disruption. Similarly, these protective effects might be associated with the involvement of attenuation of apoptosis and oxidative stress. In conclusion, LBP pre-treatment with continuous daily supplementation protected the brain and retina, both functionally and morphologically, from ischemia/reperfusion injury. This dosing regimen hold great promise in serving as a prophylactic neuroprotectant in patients at high risk for ischemic stroke, as well as preserving normal visual function and reducing irreversible neuronal death in ischemic retinopathies. Further studies on the active ingredients and underlying mechanisms would be informative for better application of LBP in clinical situation.
published_or_final_version
Ophthalmology
Doctoral
Doctor of Philosophy

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Page, Cecilia. "Histone deacetylase inhibitors as novel neuroprotective agents in in vitro and in vivo models of Parkinson's disease." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/histone-deacetylase-inhibitors-as-novel-neuroprotective-agents-in-in-vitro-and-in-vivo-models-of-parkinsons-disease(ad783896-81f9-46db-a81f-3cf7b4d372fc).html.

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Histone deacetylases (HDAC) shift the balance towards chromatin condensation and silence gene expression. Aberrant recruitment of HDACs to alter transcription suggests the use of HDAC inhibitors (HDAC-Is) as potential therapeutic candidates for neurodegenerative disorders such as Parkinson’s disease (PD). Post mortem studies of PD, characterised by progressive loss of dopaminergic neurones in the substantia nigra, have linked α-synuclein toxicity and oxidative stress to the pathogenesis of the disorder. Interestingly HDAC-Is have been shown to prevent α-synuclein and 1-methyl-4-phenylpyridinium (MPP+)-induced cellular toxicity in vitro, but there is limited reports on the inhibition HDACs in in vitro and in vivo models of PD. For this reason, the effects of the HDAC-Is, suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) were investigated in in vitro and in vivo models of PD. Neither inhibitors protected dopaminergic cell lines, SH-SY5Y and N1E-115, against hydrogen-peroxide (H2O2) and MPP+-induced toxicity. Except, at the highest concentrations (10-3M), where SAHA tended to decrease cell death. However, in the more complex rat ventral mesencephalic cultures, although HDAC-Is did not protect dopaminergic neurones against MPP+- or Lipopolysaccharide (LPS)-induced toxicity, interestingly, they reduced the number of astrocytes and activated microglia suggesting a positive anti-inflammatory effect. The effects of the HDAC-Is were then assessed in the 6-hydroxydopamine- and LPS-lesioned mouse models of PD. Both SAHA and VPA protected dopaminergic neurones and decreased the number of astrocytes in substantia nigra pars compacta (SNpc), although the number of active microglial cells were not reduced except at the highest dose of VPA. The results suggest that although the HDAC-Is, SAHA and VPA, are toxic to the immortalised dopaminergic cells in vitro, they protect nigral dopamine cells from toxin-induced cell loss in vivo. The reduction in astrocyte and microglia activation induced by the HDAC-Is suggest they may exert their protective effects by reducing inflammation associated with PD.

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Dairam, Amichand. "An investigation into the neuroprotective properties of the non-steroidal anti-inflammatory agents tolmetin, sulindac and turmeric." Thesis, Rhodes University, 2006. http://hdl.handle.net/10962/d1003230.

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Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.

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Zheve, Georgina Teurai. "Neuroprotective mechanisms of nevirapine and efavirenz in a model of neurodegeneration." Thesis, Rhodes University, 2008. http://hdl.handle.net/10962/d1003285.

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AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.

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Clarkson, Andrew N., and n/a. "Lasting neuroprotection with clomethiazole following hypoxia-ischaemia-induced neurodegeneration : a mechanistic study." University of Otago. Department of Pharmacology & Toxicology, 2005. http://adt.otago.ac.nz./public/adt-NZDU20070424.120005.

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Subsequent to an hypoxic-ischaemic (HI)-insult a multi-faceted complex cascade of events occurs that ultimately results in cellular and neurological impairments within cortical and sub-cortical central nervous system (CNS) regions. In the present studies a modified �Levine� rat-pup model of HI (left carotid artery ligation + 1 hour global hypoxia on post-natal day (PND) 26) was employed to assess the neuroprotective properties of clomethiazole (CMZ; a γ-aminobutyric acid (GABA)A receptor agonist). In this study, histological and electrophysiological paradigms were used to assess the long-term neuroprotective properties of CMZ (414mg/kg/day via mini-pumps). Key enzymes involved in inflammation, namely nitric oxide synthase (NOS) and arginase, were also examined to assess other potential CMZ mechanisms. Assessments were carried out 3- and 90-days post-HI, with extensive ipsilateral CNS lesions evident at a gross histological level, at both the early and long-term stages, with CMZ significantly decreasing the lesion size at 3- and 90-days (P<0.01; P<0.05). Evoked field potential analyses were used to assess hippocampal CA1 neuronal activity ex vivo. Electrophysiological measurements contralateral to the occlusion revealed impaired neuronal function following HI relative to short- and long-term controls (P<0.001, 3- and 14-days; P<0.01, 90-days), with CMZ providing near complete protection (P<0.001 at 3- and 14-days; P<0.01 at 90-days). Both inducible NOS (iNOS) and arginase activities were significantly increased at 3-days (P<0.01), with arginase activity remaining elevated at 90-days post-HI (P<0.05) ipsilaterally. CMZ suppressed the HI-induced increase in iNOS and arginase activities (P<0.001; P<0.05). These data provide evidence of long-term functional neuroprotection afforded by CMZ in a model of HI-induced neurodegeneration. In addition, under conditions of HI, functional deficits were not restricted to the ipsilateral hemisphere and were due, at least in part, to changes in the activity of NOS and arginase. Underlying mitochondrial dysfunction is eminently present in many neuropathological conditions. The full extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues was assessed following HI. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-days post-HI revealed a significant decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, significant changes in respiratory function were also evident in contralateral regions and cerebellum, 3-days post-HI (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I-V) and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed ipsilateral mitochondrial impairment following HI. Complexes I, II-III, V and citrate synthase were also impaired, in contralateral regions and cerebellum, 3-days post-HI. CMZ treatment provided significant protection to all mitochondrial aspects of neuronal tissue assessed. This study provides evidence of the full extent of mitochondrial damage following an HI-insult and may contribute, in part, to the impairment seen contralaterally. In addition, protection afforded by CMZ extends to preservation of mitochondrial function and integrity. Cerebral ischaemia-induced angiogenesis has been shown within and around infarcted regions and may contribute to a more favourable neurological outcome. The level of angiogenesis was examined using platelet endothelial cell adhesion molecule-1 (PECAM-1 / CD31). CD31 immunolabelling 7-days post-HI revealed a significant increase in angiogenesis compared with non-intervention controls (P<0.001). Treatment with CMZ decreased the level of angiogenesis compared to HI + saline (P<0.001) back to non-intervention control levels. Conversely, N[omega]-nitro-L-arginine methyl ester (L-NAME) treatment (5mg/kg/day) exacerbated the ischaemic lesion (P<0.001) and resulted in a marked decrease in angiogenesis compared to non-intervention controls (P<0.001). The extent of cerebral infarction in these studies is dependent on the level of NOS activity with CMZ increasing total NOS levels compared to HI + saline, while L-NAME halted the HI-induce increase in total NOS activity (P<0.001). These results show for the first time, that angiogenesis may be used as an assessment of neurodegeneration / neuroprotection in pathologies of cerebral ischaemia and are directly correlated with changes in NOS activity. These studies have therefore shown that following HI, damage also occurs contralateral to the occlusion, and is not restricted to the ipsilateral hemisphere. In addition, the neuroprotective effects of CMZ have been shown to extend out to 90-days post-HI, whereby significant protection to CA1 neuronal activity was seen. These studies also provide in vivo evidence that CMZ may also afford neuroprotection via anti-inflammatory pathways, as evidenced by a decrease in iNOS and arginase activities. Furthermore, these studies have also show evidence that angiogenesis (CD31) can be used as a diagnostic tool to assess neuroprotection / neurodegeneration.

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Song, Juxian, and 宋聚先. "Protective effects of chrysotoxine on Parkinsonian neurotoxins induceddopaminergic neuronal cell death in SH-SY5Y cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47150129.

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Scheepers, Mark Wesley. "An investigation into the neuroprotective and neurotoxic properties of levodopa, dopamine and selegiline." Thesis, Rhodes University, 2008. http://hdl.handle.net/10962/d1003267.

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a profound loss of dopaminergic neurons from the substantia nigra (SN). Among the many pathogenic mechanisms thought to be responsible for the demise of these cells, dopamine (DA)-dependent oxidative stress and oxidative damage has taken center stage due to extensive experimental evidence showing that DA-derived reactive oxygen species (ROS) and oxidized DA metabolites are toxic to SN neurons. Despite its being the most efficacious drug for symptom reversal in PD, there is concern that levodopa (LD) may contribute to the neuronal degeneration and progression of PD by enhancing DA concentrations and turnover in surviving dopaminergic neurons. The present study investigates the potential neurotoxic and neuroprotective effects of DA in vitro. These effects are compared to the toxicity and neuroprotective effects observed in the rat striatum after the administration of LD and selegiline (SEL), both of which increase striatal DA levels. The effects of exogenous LD and/or SEL administration on both the oxidative stress caused by increased striatal iron (II) levels and its consequences have also been investigated. 6-Hydroxydopamine (6-OHDA) is a potent neurotoxin used to mimic dopaminergic degeneration in animal models of PD. The formation of 6-OHDA in vivo could destroy central dopaminergic nerve terminals and enhance the progression of PD. Inorganic studies using high performance liquid chromatography with electrochemical detection (HPLC-ECD) show that hydroxyl radicals can react with DA to form 6-OHDA in vitro. SEL results in a significant decrease in the formation of 6-OHDA in vitro, probably as a result of its antioxidant properties. However, the exogenous administration of LD, with or without SEL, either does not lead to the formation of striatal 6-OHDA in vivo or produces concentrations below the detection limit of the assay. This is despite the fact that striatal DA levels in these rats are significantly elevated (two-fold) compared to the control group. The auto-oxidation and monoamine oxidase (MAO)-mediated metabolism of DA causes an increase in the production of superoxide anions in whole rat brain homogenate in vitro. In addition to this, DA is able to enhance the production of hydroxyl radicals by Fenton chemistry (Fe(III)-EDTA/H2O2) in a cell free environment. Treatment with systemic LD elevates the production of striatal superoxide anions, but does not lead to a detectable increase in striatal hydroxyl radical production in vivo. The co-adminstration of SEL with LD is able to prevent the LD induced rise in striatal superoxide levels. It has been found that the presence of DA or 6-OHDA is able to reduce lipid peroxidation in whole rat brain homogenate induced by Fe(II)-EDTA/H2O2 and ascorbate (Fenton system). However, DA and 6-OHDA increase protein oxidation in rat brain homogenate, which is further increased in the presence of the Fenton system. In addition to this, the incubation of rat brain homogenate with DA or 6-OHDA is also accompanied by a significant reduction in the total GSH content of the homogenate. The exogenous administration of LD and/or SEL was found to have no detrimental effects on striatal lipids, proteins or total GSH levels. Systemic LD administration actually had a neuroprotective effect in the striatum by inhibiting iron (II) induced lipid peroxidation. Inorganic studies, including electrochemistry and the ferrozine assay show that DA and 6-OHDA are able to release iron from ferritin, as iron (II), and that DA can bind iron (III), a fact that may easily impede the availability of this metal ion for participation in the Fenton reaction. The binding of iron (III) by DA appears to discard the involvement of the Fenton reaction in the increased production of hydroxyl radicals induced by the addition of DA to mixtures containing Fe(II)-EDTA and hydrogen peroxide. 6-OHDA did not form a metal-ligand complex with iron (II) or iron (III). In addition to the antioxidant activity and MAO-B inhibitory activity of SEL, the iron binding studies show that SEL has weak iron (II) chelating activity and that it can also form complexes with iron (III). This may therefore be another mechanism involved in the neuroprotective action of SEL. The results of the pineal indole metabolism study show that the systemic administration of SEL increases the production of N-acetylserotonin (NAS) by the pineal gland. NAS has been demonstrated to be a potent antioxidant in the brain and protects against 6-OHDA induced toxicity. The results of this study show that DA displays antioxidant properties in relation to lipid eroxidation and exhibits pro-oxidant properties by causing an increase in the production of hydroxyl radicals and superoxide anions, as well as protein oxidation and a loss of total GSH content. Despite the toxic effects of DA in vitro, the treatment of rats with exogenous LD does not cause oxidative stress or oxidative damage. The results also show that LD and SEL have some neuroprotective properties which make these agents useful in the treatment of PD.

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Wang, Ziying. "Neuroprotective effects of a novel TFEB activator E4 and its self-carried nanoparticles in MPTP-induced Parkinson's disease models." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/695.

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Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by cell death in the substantia nigra pars compacta (SNpc) and the appearance of aggregated α-synuclein (α-syn). Autophagosomes accumulation and lysosomal reduction were discovered in PD patients' brain, which indicated the deficiency of autophagy in the progress of PD. TFEB (transcription factor EB) is a member of basic helix -loop-helix-leucine-zipper transcription factors (MiT family) and is a key master monitor for autophagy and lysosome biogenesis. Overexpression of TFEB is able to rescue the dopaminergic neurons (DAs) loss and α-syn aggregated in α-syn transgenic mice model and MPTP PD model. Hence, in recent years, many researchers have considered TFEB as a new therapeutic target for PD In this study, we discovered a novel TFEB activator named E4 by screening synthesized curcumin analogs. We have found that E4 strongly promoted TFEB nuclear translocation and induced autophagy in different cell lines. TFEB is essential for E4-induced autophagy flux. We also demonstrated that the underlying mechanism of E4 activate TFEB is mainly through inhibiting mTORC1 activity. We constitutively activate mTOR by knockdown TSC2 abrogated the increase of LC3-II and decrease of p-TFEB. We further estimated the protective effects of E4 in overexpressed α-syn model and neurotoxins induced cytotoxicity model. Treated with E4 for 48h in N2a transfected with A53T α-synuclein cells dose-dependently reduce the α-synuclein level. At the same time, we established the MPP+ model in PC12 cells which is pre-treated cell with E4 for 6 hours and then co-treated cells with MPP+ for 48 hours. The cell viability results showed that E4 significantly protect PC12 cells against MPP+ cytotoxicity dose-dependently. E4 had shown good neuroprotective effects in PD in vitro models while poor water solubility and low brain permeability restricted its application in PD animal models. Hence, assembling E4 molecules into self-carried nanoparticles (NanoE4) addressed the issue of poor water solubility and intranasal administration solved the problem of low permeability. In order to track NanoE4 release in vitro and in vivo, we further investigated the absorption and emission of NanoE4. However, the absorption fluorescence results showed that NanoE4 exhibits the strong aggregation-caused quenching effect (ACQ) due to π-π stacking of the planar molecule within the NPs. NanoE4 have much weak emission compared with E4 molecules. Therefore, we fabricated E4-TPAAQ NPs by co-reprecipitating E4 molecules with the reported fluorescent organic compound TPAAQ (2,6-Bis[4-(diphenylamino) phenyl] anthraquinone). Next, we developed an intranasal drug delivery system in our lab. After intranasal co-drop nanodrug E4-TPAAQ NPs for 24 hours, we observed strong fluorescence distributed in the brain which indicated that deliver nanoparticles into the brain successfully through nasal-brain system. Therefore, we examined the protective effect of NanoE4 in MPTP-induced PD mice model. In MPTP models, we found autophagy dysfunction, motor function decrease and increase of α-synuclein as reported previously. Treatment with NanoE4 rescued the motor dysfunction induced by MPTP. NanoE4 also increase TH level in the striatum part of midbrain. NanoE4 treatment also decreased the α-synuclein protein aggregate in both SNpc and striatum. Overall, these results demonstrate the neuroprotection NanoE4 against PD. Collectively, our findings 1) discovered a novel TFEB activator E4 that inhibited the mTOR pathway 2) indicated in vitro and in vivo experimental evidence for TFEB activator as the anti-PD drug candidate 3) provide a novel drug develop and delivery system for potential PD that limited by water solubility and BBB (blood-brain barrier) obstacle

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Kamdem, Jean Paul. "Antioxidant and neuroprotective properties of trichilia catigua (catuaba) against ischemia-reperfusion and pro-oxidants agents in rat hippocampal slices." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/78130.

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Plantas medicinais apresentam efeitos benéficos contra a patofisiologia de várias doenças induzida pelo estresse oxidativo incluindo isquemia-reperfusão (I/R). Trichilia catigua, popularmente conhecida no Brasil como “catuaba”, é amplamente utilizada como um neuroestimulante e afrodisíaco. Infusões da casca são popularmente utilizadas na medicina popular contra debilidade sexual, cansaço, insônia, estresse e deficiências relacionadas à memória e sistema nervoso central. Porém, o envolvimento da atividade antioxidante de T. catigua em suas propriedades farmacológicas especialmente em relação ao sistema nervoso ainda é escasso na literatura. Sendo assim, a primeira parte deste estudo investigou o pontencial antioxidante de T. catigua usando modelos químicos e biológicos. Como resultado, foi demonstrado que o extrato etanólico e diferentes frações da casca de T. catigua eliminaram o radical 1,1-difenil-2-picrilhidrazila (DPPH), e inibiram a geração de substâncias reativas ao ácido tiobarbitúrico (TBARS) causadas pelo Fe2+ em homogenatos dos cérebros de rato. O extrato etanólico apresentou a maior atividade antioxidante. Além disso, o extrato etanólico inibiu a produção de espécies reativas de oxigênio/nitrogênio (EROS/ERNS) induzidas pelo Ca2+ e diminuiu o potencial de membrana (ΔΨm) mitocondrial nas maiores concentrações. Com base nos resultados acima, nós hipotetizamos que o extrato etanólico de T. catigua pode, pelo menos, reduzir consideravelmente os danos oxidativos induzidos pela isquemia reperfusão (I/R) em fatias de hipocampo de rato através da atenuação da produção de EROS/ERNS. Baseado nisso, a segunda parte deste estudo investigou o efeito protetor do extrato etanólico de T. catigua contra os danos oxidativos induzidos por I/R em fatias de hipocampo de ratos. Como resultado foi demonstrado que T. catigua previniu os efeitos deletérios causados por I/R nas fatias de hipocampo, através do aumento da viabilidade mitocondrial, o qual foi associado com o decréscimo na liberação de lactato desidrogenase (LDH) no meio de incubação; pelo decréscimo da oxidação de DCFH no meio; e aumento do conteúdo de tióis não proteicos (NPSH) em fatias homogeneizadas. No entanto, T. catigua não foi capaz de proteger as fatias da I/R quando adicionadas ao meio após da injúria isquêmica, sendo assim, sugerindo que ela possa ser usada somente como preventiva e não como agente curativo frente ao dano cerebral. Uma vez que alterações de aprendizado e memória são consequências comuns a uma variedade de doenças e agressões tóxicas, a terceira parte deste estudo concentrou-se em determinar se T. catigua ofereceria neuroproteção contra o estresse oxidativo induzido por diferentes pro-oxidantes. Os resultados indicaram que a exposição de fatias de hipocampo de rato por 1h ao peróxido de hidrogênio (H2O2), nitroprussiato de sódio (NPS) e ácido 3-nitropropiônico (3-ANP) diminui a atividade mitocondrial; aumentou a geração de ROS/RNS no meio de incubação e causou a formação de TBARS nas fatias homogeneizadas. A diminuição destes efeitos deletérios foi significativa quando as fatias foram pré-tratadas com o extrato etanólico de T. catigua. Em conclusão, nossos resultados demonstraram que o uso do extrato de T. catigua pode ser benéfico na prevenção de desordens neurológicas associadas ao estresse oxidativo, e que seus efeitos benéficos parecem estar associados, pelo menos em parte, a sua atividade antioxidante, que, por sua vez, podem ser atribuídas ao conteúdo polifenólico da planta.
Medicinal plants have been shown to have beneficial effects against oxidative stress-induced pathophysiology of various diseases including brain ischemia-reperfusion (I/R). Trichilia catigua, popularly known in Brazil as “catuaba”, is widely used as a neurostimulant and aphrodisiac. Infusions of the bark are popularly used in folk medicine against sexual weakness, exhaustion, insomnia, stress, memory and central nervous systems disabilities. However, the involvement of antioxidant ability of T. catigua in its pharmacological properties especially in the management of neurological-related diseases is scanty in the literature. In this context, the first part of this study investigated the potential antioxidant activity of T. catigua using chemical and biological models. As a result, we have demonstrated that ethanolic extract and different fractions from the stem bark of T. catigua scavenged the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, and inhibited the formation of thiobarbituric acid reactive substances (TBARS) caused by Fe2+ in rat’s brain homogenates. However, ethanolic extract exhibited the highest antioxidant activity. In addition, ethanolic extract inhibited Ca2+-induced reactive oxygen/nitrogen species (ROS/RNS) generation and caused a decrease in the mitochondrial membrane potential (ΔΨm) only at high concentrations. On the basis of the aforementioned results, we hypothesized that ethanolic extract from T. catigua may at least, markedly reduce oxidative damage induced by in vitro I/R in rat hippocampal slices through attenuation of ROS/RNS production. Thus, the second part of this study investigated the protective effects of ethanolic extract of T. catigua against oxidative damage induced by I/R in rat hippocampal slices. T. catigua prevents hippocampal slices from the deleterious effects caused by I/R, by increasing mitochondrial viability, which was associated with decreased lactate dehydrogenase (LDH) leakage in the incubation medium; by decreasing DCFH oxidation in the medium, and increasing non-protein thiols (NPSH) content in slices homogenates. In contrast, T. catigua could not protect slices from I/R when it was added to the medium after ischemic insult, suggesting that it can only be used as preventive and not as curative agent against brain damage. Taking that alteration in learning and memory function are common consequences of a wide variety of toxic insults and disease states, the third part of this study was undertaken to determine whether T. catigua offered neuroprotection against oxidative stress induced by different pro-oxidants. Exposure of rat hippocampal slices for 1 h to hydrogen peroxide (H2O2), sodium nitroprusside (SNP) and 3-nitropropionic acid (3-NPA) decreased mitochondrial activity, increased ROS/RNS in the incubation medium and caused TBARS formation in rat hippocampal slices homogenates. These deleterious effects were significantly attenuated by pre-treatment of slices with ethanolic extract of T. catigua. Overall, our data showed that the use of T. catigua extract may be beneficial in preventing neurological disorders associated with oxidative stress, and that its beneficial effects seems to be related at least, in part, to its antioxidant activity, which can be attributed to its polyphenolic content.

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42

Sutherland, Brad Alexander, and n/a. "Heme oxygenase and the use of tin protoporphyrin in hypoxia-ischaemia-induced brain damage : mechanisms of action." University of Otago. Department of Pharmacology & Toxicology, 2009. http://adt.otago.ac.nz./public/adt-NZDU20090119.150318.

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Stroke is the third largest cause of death, and the leading cause of disability worldwide. Treatments are sought to reduce mortality, and increase survival time following an ischaemic stroke. Hypoxia-ischaemia (HI) is the combination of cerebral ischaemia and global hypoxia that can lead to neuronal damage, particularly perinatally. The complex neurodegenerative cascade following ischaemic stroke and HI activates many stress pathways, including heme oxygenase (HO). HO metabolises free heme to release iron, carbon monoxide, and biliverdin, which is subsequently metabolised to bilirubin. This thesis aims to elucidate the role HO plays following HI, and assess any neuroprotective mechanisms using HO modulators. The 26 day old rat model of HI was used to induce the neurodegenerative cascade. All animals were sacrificed 3 days post-insult. Immunohistochemistry and Western blotting demonstrated that HO-1 was increased in the ipsilateral hemisphere of both HI (by 1.7 � 0.1 fold: p = 0.016, n = 4) and middle cerebral artery occlusion (MCAO) brains (by 1.6 � 0.1 fold: p = 0.037, n = 4), compared to controls. HO-2 was constitutively expressed throughout the control brain, but HI upregulated HO-2 expression (by 1.7 � 0.2 fold: p = 0.027, n = 4) ipsilaterally, whereas MCAO did not alter HO-2 expression. Administration of the HO inhibitor tin protoporphyrin (SnPP; 30[mu]mol/kg intraperitoneally) daily, beginning 1 day prior to HI until sacrifice, reduced infarct volume to 50% � 10 of saline-treated animals (p = 0.039, n = 6-8). The HO inducer ferriprotoporphyrin (FePP; 30[mu]mol/kg) had no effect on infarct volume. HO activity and protein expression were not significantly altered following treatment with SnPP. Therefore, the neuroprotective actions of SnPP may be through alternative mechanisms. SnPP treatment increased HI + saline-induced total nitric oxide synthase (NOS) activity by 1.5 � 0.06 fold (p < 0.001, n = 6-8). Conversely, SnPP inhibited both inducible NOS (50% � 7 of HI + saline; p = 0.045, n = 7-8) and cyclooxygenase (COX) activity (32% � 6 of HI + saline; p = 0.049, n = 4-8). SnPP treatment also increased mitochondrial complex I activity by 1.6 � 0.25 fold (p = 0.04, n = 4-8) and complex V activity by 1.7 � 0.26 fold (p = 0.046, n = 4-8) in the ipsilateral hemisphere. It appears that SnPP is acting on inflammatory and mitochondrial enzymes to produce neuroprotection. In vitro analysis of cultured RAW264.7 macrophages exposed to lipopolysaccharide (LPS; 10[mu]g/mL) treated with SnPP (dose range: 10⁻�⁰M - 10⁻⁵M) did not alter nitrite levels or cell viability. However, high dose SnPP (10⁻⁵M) in the absence of LPS increased nitrite levels from control cells by 2.7 � 0.7 fold (p = 0.043, n = 6), complementing the in vivo total NOS data. Other mechanisms such as NMDA receptor activation were not affected by 100[mu]M SnPP or 100[mu]M SnCl₂ in patch clamped cortical pyramidal neurons. Overall, the role that HO plays following HI remains unclear, but this thesis provides definitive evidence that SnPP (an established HO inhibitor) provides neuroprotection. This neuroprotection may be due to its effects on inducible pathways such as NOS and COX. Therefore, further experimentation is required to fully elucidate the role that HO plays following cerebral ischaemia, and additional in vivo evidence will be necessary to establish HO inhibitors as a putative candidate for cerebral ischaemia neuroprotection.

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43

Mi, Xuesong, and 米雪松. "Neurodegeneration and neuroprotection in glaucoma retinopathy-probing the role of endothelin-1, RAGE, A{221} and lycium barbarum." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47243922.

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In order to understand the possible mechanisms in the glaucoma-related retinopathy, the role of the vasoconstrictor, endothelin-1 (ET-1), receptor for advanced glycation end-products (RAGE) as well as its ligand, Aβ in the degeneration of retinal ganglion cells (RGCs) were studied in experimental models. In addition, the relationship of ET-1, RAGE and Aβ for the RGC protective mechanism of Lycium Barbarum (LB) was also investigated. In the first part, ET-1 together with its receptors, ETA and ETB, were studied to understand their possible roles in chronic ocular hypertension (COH). The neuronal protective mechanism of LB was also determined by using a well established COH rat model. In normal rats, ET-1 and its receptors, ETA and ETB, were distributed in the retina, vasculature and optic nerve. Interestingly, ET-1 expression was up-regulated after COH. LB could decrease the expression of ET-1 and regulate its receptors (up-regulation of ETB and down-regulation of ETA in vasculature; up-regulation of ETA and down-regulation of ETB in RGCs) under the condition of COH. These data suggested that the RGC protective mechanism of LB might be related to its ability to regulate the biological effects of ET-1. To investigate the pathogenic effect of ET-1 in glaucoma, in the second part, we used transgenic mice with over-expression of ET-1 on endothelial cells (TET-1 mice). We found that beginning at 10-12 months, TET-1 mice showed a progressive retinal degeneration (loss of RGCs associated with neurons in the inner nuclear layer and outer nuclear layer of the retina) without elevation of the intraocular pressure (IOP). The data demonstrated that TET-1 mice may serve as a potential model to investigate the role of endothelial ET-1 in the pathogenesis of normal tension glaucoma and other degenerative retinopathy. To investigate whether LB plays a role on neuronal protection other than in COH, in the third part, we used an acute ocular hypertension (AOH)-induced ischemia mouse model. We found that LB could rescue RGCs under AOH insult, associating with blood vessel protection (decreasing the damage of blood-retinal-barriers and rescuing the survival of endothelial cells and pericytes) and inhibiting retinal gliosis. We also found the protective mechanism of LB was closely correlated with down-regulation of the expression of RAGE, ET-1, APP (amyloid precursor protein), AGE (advanced glycation end-product) as well as Aβ; therefore to reduce the damage effects of these RAGE-mediated reactions to the retinal neurons, blood vessels and glial cells involved in the ischemic insult. Taken together, the present study demonstrated that TET-1 mice may be a potential model for investigating the role of ET-1 in degenerative retinopathies, such as normal tension glaucoma. We also showed the neuronal protective mechanism of LB in vivo was associated with inhibiting the biological effect of ET-1 and down-regulating the damage signaling pathways mediated by the activation of RAGE and its ligands (AGE and Aβ). These results provided further understandings in the mechanism of the glaucoma-related retinopathy. In addition, LB could be a neuroprotective agent to the retina following both chronic and acute injuries.
published_or_final_version
Anatomy
Doctoral
Doctor of Philosophy

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44

Sartori, César Renato 1973. "Atividade fisica e neuroproteção em camundongos adultos após indução de status epilepticus por pilocarpina." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314234.

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Orientador: Francesco Langone
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-04T18:58:52Z (GMT). No. of bitstreams: 1 Sartori_CesarRenato_M.pdf: 1900704 bytes, checksum: 51c83a46f04b1d713501125ed8970eb3 (MD5) Previous issue date: 2005
Resumo: O modelo de epilepsia induzida por pilocarpina em camundongos reproduz a Epilepsia do Lobo Temporal (ELT) em humanos. Animais submetidos à indução de status epilepticus apresentam alterações comportamentais, eletroencefalográficas e lesão neuronal compatíveis com esta condição. Estudos recentes relatam relevantes efeitos positivos da prática de atividade física sobre o sistema nervoso tanto em humanos como em modelos animais. Dentre estes efeitos figuram o aumento da sobrevivência neuronal e da resistência cerebral a diferentes insultos, promoção da angiogênese, estímulo da neurogênese, fortalecimento da potenciação de longa duração no hipocampo, melhora da aprendizagem e memória e contribuição para a manutenção da função cognitiva durante o envelhecimento. Todos estes efeitos conferem à atividade física um grande potencial neuroprotetor. Além disso, foram relatados benefícios decorrentes desta intervenção ambiental diretamente em pacientes com epilepsia e em animais submetidos à epilepsia induzida. Contudo, não há dados na literatura sobre o possível efeito neuroprotetor da atividade física no modelo de epilepsia induzida por pilocarpina em camundongos. Assim sendo, o presente estudo teve por objetivo investigar os efeitos da atividade física voluntária crônica sobre a perda neuronal no hipocampo e suas conseqüências na função mnemônica de camundongos submetidos a este modelo experimental. Trinta e dois camundongos Swiss foram divididos em quatro grupos experimentais (n=8): Saudável Sedentário (SS), Saudável Corredor (SC), Epiléptico Sedentário (ES) e Epiléptico Corredor (EC). Quarenta e oito horas após a indução do status epilepticus, ou sua simulação, foi proporcionado aos animais dos grupos corredores (SC e EC) o acesso a uma roda de atividade instalada em suas respectivas gaiolas por um período de 28 dias. Após este período os animais foram testados no labirinto aquático de Morris para avaliação da memória de referência espacial. Ao final dos testes os animais foram perfundidos com paraformaldeído (4% em tampão fosfato) e os cérebros removidos e processados para inclusão em parafina. Foram então obtidos cortes frontais do cérebro (8µm) para avaliação da extensão da lesão tecidual (coloração de Nissl), da presença de neurônios em degeneração (Fluoro Jade B) e da proliferação celular (PCNA) na formação hipocampal dorsal. Os animais dos grupos SS e SC não apresentaram lesão neuronal ou neurodegeneração, como esperado; também não diferiram entre si na proliferação celular e no teste de memória de um modo geral. Os animais dos grupos ES e EC apresentaram lesão neuronal e neurodegeneração, não sendo constatadas diferenças entre sedentários e corredores. Por outro lado, os animais ES revelaram maior proliferação celular comparados aos EC. Os animais do grupo EC apresentaram desempenho significativamente melhor nos testes de memória quando comparados aos animais ES. Assim, nossos dados revelaram que, a despeito de não ter ocorrido proteção contra lesão histológica, a atividade física melhorou significantemente o desempenho dos animais submetidos ao status epilepticus no teste do labirinto aquático de Morris, indicando que mesmo após lesão neurológica a atividade física promove melhora funcional. Acreditamos que tal melhora pode ser atribuída a mecanismos moleculares relacionados à plasticidade neuronal, que não foram identificados pelas técnicas utilizadas no presente estudo
Abstract: Pilocarpine-induced epilepsy in mice is an experimental model of the Temporal Lobe Epilepsy (TLE). Status epilepticus determined by pilocarpine adminstration leads to behavioral and electroencephalographic changes and neuronal damage similar to those observed in TLE. Recently, it has been shown that physical activity exerts neuroprotective effects, such as increase in neuronal survival, angiogenesis and neurogenesis; resistance to brain injuries, strengthening of the long term potentiation (LTP), improvement of memory and learning; and preservation of cognitive function during aging process. Particularly, physical activity also plays a positive role in epileptic patients and animals. However, there are no reports regarding the neuroprotective action of physical activity on the pilocarpine model of epilepsy in mice. In the present work, we studied the effects of the voluntary physical activity on hippocampal neuronal loss and mnemonic function of mice after the pilocarpine-induced status epilepticus. Thirty-two Swiss mice were assigned to four experimental groups (n=8): Normal Sedentary (NS), Normal Runner (NR), Epileptic Sedentary (ES) and Epileptic Runner (ER). Forty-eight hours after the status epilepticus or its simulation the animals of the runner groups (NR, ER) had access to a running wheel for 28 days. After that, the mice were submitted to the Morris Water Maze test for the evaluation of the spatial memory. Finally, the mice were perfused with paraformaldehyde (4% in phosphate buffer), the brains were dissected and processed for paraffin embedding. Frontal sections (8mm) were serially cut and used for analysis of histologic damage (Nissl staining), degenerating neurons (Fluoro Jade B) and cell proliferation (immunohistochemistry for PCNA) of the dorsal hippocampal formation. Mice of the NS and NR groups showed neither neuronal damage nor neurodegeneration. In addition, these groups were similar to each other in the Morris Water Maze test and exhibited comparable immunostainig patterns for PCNA. In contrast to the previous groups, in ES and ER groups neuronal damage and neurodegeneration were observed and equivalent. However, cell proliferation was higher in ES than in ER. Animals of the ER group had better performance in the Morris Water Maze test compared to ES mice. In conclusion, our results show that physical activity improved significantly the spatial memory of mice that had status epilepticus induced by pilocarpine, despite of having not changed the morphological evidence of neuronal damage. We believe that such improvement might be attributed to molecular mechanisms related to neuronal plasticity, which were not identified by the techniques we used in the present investigation
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular

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45

Lorente, Picon Marina. "Neuroprotective effect of stomatin-like protein 2 overexpression in A53T-a-synuclein parkinson disease mice model." Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/66338.

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46

Kundrotienė, Jurgita. "Ischemic brain damage following transient and moderate compression of sensorimotor cortex in Sprague-Dawley and diabetic Goto-Kakizaki rats /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-819-X/.

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47

Avery, Michelle A. "Axon Death Prevented: Wld^s and Other Neuroprotective Molecules: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/520.

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A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed ‘Wallerian degeneration,’ whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wlds) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such as progressive motor neuronopathy), Wlds is able to delay disease onset (for a review, see Coleman, 2005). Wlds has been cloned and was found to be a fusion event of two neighboring genes: Ube4b, which encodes an ubiquitinating enzyme, and NMNAT-1 (nicotinamide mononucleotide adenylyltransferase-1), which encodes a key factor in NAD (nicotinamide adenine dinucleotide) biosynthesis, joined by a 54 nucleotide linker span (Mack et al., 2001). To address the role of Wlds domains in axon protection and to characterize the subcellular localization of Wlds in neurons, our lab developed a novel method to study Wallerian degeneration in Drosophila in vivo (MacDonald et al., 2006). Using this method, we have discovered that mouse Wlds can also protect Drosophila axons for weeks after acute injury, indicating that the molecular mechanisms of Wallerian degeneration are well conserved between mouse and Drosophila. This observation allows us to use an easily manipulated genetic model to move the Wlds field forward; we can readily identify what Wlds domains give the greatest protection after injury and where in the neuron protection occurs. In chapter two of this thesis, I identify the minimal domains of Wlds that are needed for protection of severed Drosophila axons: the first 16 amino acids of Ube4b fused to Nmnat1. Although Nmnat1 and Wlds are nuclear proteins, we find evidence of a non-nuclear role in axonal protection in that a mitochondrial protein, Nmnat3, protects axons as well as Wlds. In chapter 3, I further explore a role for mitochondria in Wlds-mediated severed axon protection and find the first cell biological changes seen in a Wlds-expressing neuron. The mitochondria of Wlds- and Nmnat3-expressing neurons are more motile before injury. We find this motility is necessary for protection as suppressing the motility with miro heterozygous alleles suppresses Wldsmediated axon protection. We also find that Wlds- and Nmnat3- expressing neurons show a decrease in calcium fluorescent reporter, gCaMP3, signal after axotomy. We propose a model whereby Wlds, through production of NAD in the mitochondria, leads to an increase in calcium buffering capacity, which would decrease the amount of calcium in the cytosol, allowing for more motile mitochondria. In the case of injury, the high calcium signal is buffered more quickly and so cannot signal for the axon to die. Finally, in chapter 4 of my thesis, I identify a gene in an EMS-based forward genetic screen which can suppress Wallerian degeneration. This mutant is a loss of function, which, for the first time, definitively demonstrates that Wallerian degeneration is an active process. The mammalian homologue of the gene encodes a mitochondrial protein, which in light of the rest of the work in this thesis, highlights the importance of mitochondria in neuronal health and disease. In conclusion, the work presented in this thesis highlights a role for mitochondria in both Wlds-mediated axon protection and Wallerian degeneration itself. I identified the first cell biological changes seen in Wlds-expressing neurons and show that at least one of these is necessary for its protection of severed axons. I also helped find the first Wallerian degeneration loss-of-function mutant, showing Wallerian degeneration is an active process, mediated by a molecularly distinct axonal degeneration pathway. The future of the axon degeneration field should focus on the mitochondria as a potential therapeutic target.

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Vázquez, Jiménez Laura. "Studies on the Chemical Modulation of Neuroprotective Agents Related to CR-6 Addressed to Improve the Delivery through the Blood-Brain Barrier." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/285339.

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Oxidative stress is one of the most important factors in degenerative diseases like cancer, Alzheimer or in episodes like ischemia. During these processes, reactive species of oxygen (ROS) and nitrogen (RNS) are generated. This fact can cause the chemical modification of important biomolecules, in particular lipids and proteins. The strategy that involves the use of antioxidants and neuroprotective agents to fight against the lesive effects of these species stumbles over the blood-brain-barrier (BBB). This barrier protects the brain from the action of a wide variety of organic molecules and drugs. Thus, it is important to develop novel antioxidant agents with good delivery through the BBB. In our group it was discovered the antioxidant agent 3,4-dihydro-2,2-dimethyl-7-metoxy-1-(2H)-benzopyran (CR-6), an analogue of alpha- and gamma-tocopherols (Figure 1), which is currently used in dermopharmacy and it is also in a phase II trials for anticancer treatment (combined with other drugs). In our present project, one of the main goals is the synthesis of a short library of CR-6 analogues that could improve the pass through the BBB. Accordingly, fourteen novel CR-6 analogues have been synthesized introducing essential nutrients for brain that work as BBB-shuttles at C2 of CR-6 scaffold. The antioxidant activity was evaluated to assure that it does not change by the incorporation of variability at C2 position (the DPPH assay and the in vitro CAA were used). In addition, the BBB permeability was evaluated to compare the BBB bioavailability of these new antioxidant agents with the references CR-6 and Trolox (PAMPA, Caco-2 and BBCEC assays were used).
El estrés oxidativo es uno de los factores etiológicos más importantes en las enfermedades degenerativas como el cáncer, el Alzheimer o en episodios de isquemia. Durante estos procesos, se generan especies reactivas de oxigeno (ROS) y de nitrógeno (RNS) que provocan modificaciones de las biomoléculas como los lípidos, las proteínas y el ADN. El uso de agentes antioxidantes y neuroprotectores ayudan a reducir los efectos lesivos que el estrés oxidativo tiene en el cerebro, por ejemplo. La barrera hematoencefálica o BBB protege al cerebro de la acción de una amplia variedad de moléculas orgánicas y fármacos. Por ello, existe un gran interés en el desarrollo de nuevos agentes antioxidantes con un buen transporte a través de la BBB. En nuestro grupo de investigación se ha desarrollado el agente antioxidante 3,4-dihidro-2,2-dimetil-7-metoxi-1-(2H)-benzopirano (CR-6), un análogo de alfa- y gamma-tocoferol, que en la actualidad se emplea en dermofarmacia y se encuentra en ensayos de fase II para el tratamiento del cáncer (combinado con otros fármacos). En este proyecto se persigue la síntesis de una colección de análogos del CR-6 que mejoren el paso a través de la BBB. De este modo, se han sintetizado catorce compuestos derivados del CR-6 introduciendo nutrientes esenciales del cerebro que actúan como transbordadores de la BBB. La actividad antioxidante de todos estos compuestos se ha evaluado para asegurar que ésta se mantiene al introducir variabilidad en la posición C2 mediante los ensayos del DPPH y el in vitro CAA. A su vez, la permeabilidad de la BBB se ha evaluado para compararla con los compuestos de referencia CR-6 y Trolox a partir de los ensayos in vitro Caco-2, PAMPA y BBCEC.

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Galpern, Wendy R. "Neuroprotection and Neurotransplantation Strategies in Models of Parkinson’s Disease." eScholarship@UMMS, 1996. https://escholarship.umassmed.edu/gsbs_diss/143.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic cell death in the substantia nigra pars compacta (SNc) and dopamine (DA) depletion in the striatum. Current pharmacological treatments are aimed at the replacement of striatal DA via the administration of levodopa. While this therapy is beneficial initially, long-term treatment is associated with significant side effects, and disease progression continues. The present experiments investigate neuroprotective and neurotransplantation strategies as alternatives to palliative pharmacologic treatments. The optimal therapeutic approach to neurodegenerative diseases would be to protect against cell death and prevent disease progression. PD is well-suited for such neuroprotective strategies as primarily one cell population is affected in this disorder. Neurotrophic factors (NTFs) have been identified which support dopaminergic neuronal survival in vitro. In the present studies, the neuroprotective effects of the neurotrophin brain-derived neurotrophic factor (BDNF) have been evaluated in a 1-methyl-4-phenylpyridinium (MPP+) model of substantia nigra (SN) degeneration. BDNF-secreting fibroblasts were implanted dorsal to the SN prior to the infusion of the mitochondrial complex I inhibitor MPP+. Subsequent histological analysis demonstrated that BDNF is able to attenuate MPP+ induced dopaminergic cell loss in the SNc. Moreover, neurochemical evaluation demonstrated that BDNF is able to enhance DA levels in the remaining SN neurons in this same paradigm. The cause of cell death in neurodegenerative diseases likely involves the interaction of mitochondrial impairment, excitotoxicity, and oxidative stress. In order to evaluate the mechanism of NTF-mediated protection, the ability of nerve growth factor (NGF) to attenuate the production of the oxidant peroxynitrite was evaluated in a model of mitochondrial impairment. NGF was found to decrease the production of 3-nitrotyrosine, the product of peroxynitrite mediated tyrosine nitration. Thus, NTF-mediated neuroprotection may act in part by decreasing reactive oxygen species and oxidative stress. At present, neuroprotective therapies are not clinically available. An alternate therapeutic approach to PD is the replacement of striatal DA and reconstruction of synaptic circuitry via the intrastriatal transplantation of fetal dopaminergic neurons. Current transplantation protocols using human fetal tissue are constrained by limited tissue availability. In order to investigate an alternate cell source for the treatment of PD, fetal porcine dopaminergic neurons were implanted into the DA depleted striatum of 6-OHDA lesioned rats. Amphetamine-induced rotational recovery was monitored, and graft survival was evaluated 19 weeks after grafting. In immunosuppressed rats, porcine dopaminergic neurons were found to attenuate rotational deficits and extensively reinnervate the host striatum. The neuroprotective effects of BDNF suggest that NTFs may be important mediators of dopaminergic neuronal survival and function in the adult brain. However, several conditions including appropriate dosage and delivery need to be determined before clinical applications may be achieved. As an alternative to neuroprotection, neurotransplantation not only restores striatal DA but also reconstructs the synaptic circuitry of the basal ganglia. The finding that porcine dopaminergic neurons survive with in adult host brain, reinnervate the DA depleted striatum, and mediate functional recovery suggests that porcine DA neurons may serve as an alternate cell source for transplantation in PD.

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Macri, Fábio Teixeira. "Estudo do efeito neuroprotetor da estimulação magnética transcraniana e hipotermia em modelo de isquemia cerebral induzida." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5166/tde-05092011-154945/.

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Introdução: Muitos estudos veem sendo realizados com a finalidade de identificar agentes que possam ter efeito benéfico no tratamento ou prevenção das lesões causadas nos neurônios devido à isquemia. A hipotermia já demonstrou resultados consistentes em estudos experimentais e a Estimulação Magnética Transcraniana (EMTr) já foi usada visando reduzir danos em neurônios hipocampais de animais submetidos a isquemia cerebral. Com a propriedade de aumentar ou diminuir a excitabilidade cortical a partir do estímulo magnético, estima-se que ocorra uma interferência na produção de alguns neurotransmissores e receptores de membrana, que promoveriam efeito protetor a estas células. Neste estudo avaliamos a capacidade da EMTr de proteger os neurônios de uma lesão por hipóxia, e sua possível interferência no efeito protetor da hipotermia, tentando identificar alguns mecanismos que possivelmente estariam envolvidos neste fenômeno. Métodos: Como modelo de isquemia, foram utilizados Gerbils previamente submetidos a uma avaliação de comportamento e memória por meio do teste de esquiva. O protocolo de EMTr foi a partir de sessões diárias com 25 séries de 5 segundo a 25Hz, com um intervalo de 45 segundos entre as séries, por sete dias consecutivos, com um total de 21 875 pulsos com uma intensidade de 100% do limiar motor, e sendo realizada a indução da isquemia logo após o término da última sessão, ou na isquemia após a EMTr, em sessões diárias com 25 séries de 5 segundos a 25Hz, com um intervalo de 45 segundos entre as séries, durante 3 dias consecutivos, começando imediatamente após a cirurgia. Foi mantida a temperatura de 36 °C durante o período de oclusão do vaso e os 30 minutos consecutivos, ou 31 a 32 °C quando em hipotermia. O preparo das lâminas teve cortes envolvendo a região do hipocampo, corados com hematoxilina e eosina, além de outros preparos, a marcação de TUNEL e Caspase, que visam evidenciar a ocorrência de apoptose. Resultados: Embora sem significância estatística, os animais que receberam EMTr aparentemente tiveram uma melhor performance no teste da esquiva, principalmente se aplicado após a indução da isquemia. A hipotermia demonstrou uma eficiência significativa, tanto na análise histológica quanto no teste da esquiva, associado ou não à EMTr, e nestes animais submetidos a isquemia durante a hipotermia, os que receberam EMTr tiveram área de sobrevida no hipocampo significativamente maior na análise histológica com hematoxilina e eosina. Nos animais submetidos à isquemia durante a temperatura normal, a EMTr não demonstrou aumentar a área de sobrevida das células do hipocampo. Conclusões: A EMTr (ativa ou placebo, prévia ou posterior à isquemia) pareceu ter um efeito positivo no teste de esquiva. O procedimento de estimulação pareceu bastante traumático e estressante para os animais, tendo ocorrido alguns óbitos durante a imobilização, provavelmente por asfixia. A EMTr apresentou efeito protetor significativo apenas nos animais submetidos a isquemia durante hipotermia
Introduction: Over the time many researches have been conducted with the aim of identifying agents that may have beneficial effects in the treatment or prevention of cerebral ischemia, hypothermia has shown consistent results in experimental trials and Repetitive Trans Cranial Magnetic Stimulation (rTMS) has been used in a study attempting to reduce damage in hippocampal neurons. With the property to increase or decrease cortical excitability from the repetitive magnetic stimulus, it is estimated that an interference occurs in the production of some neurotransmitters and receptors of neuronal membrane, which therefore protects these cells from hypoxia. In this study we evaluated the ability of rTMS to protect neurons from injury due to hypoxia, and its possible interference in the protective effect of hypothermia and we tried to identify some mechanisms that possibly are involved in this phenomenon. Methods: Ischemia model was performed using Gerbil that was subsequently submitted to an evaluation of behavior and memory through passive avoidance task. The rTMS protocol was daily sessions with 25 series of 5 seconds at 25Hz with an interval of 45 seconds between series, for 7 consecutive days, with a total of 21 875 pulses with an intensity of 100% of motor threshold, and being carried through the induction of ischemia soon after the end of the last session, or rTMS after ischemia, in daily sessions with 25 series of 5 seconds at 25Hz with an interval of 45 seconds between series, for 3 consecutive days, starting immediately after surgery. The temperature of 36 °C was maintained during the period of vessel occlusion and subsequent 30 minutes, or 31 °C to 32 °C when in hypothermia. The preparation of the slices had sections of the region involving the hippocampus, stained with hematoxylin and eosin in addition to other preparations, TUNEL and caspase, which aim to evidence the occurrence of apoptosis. Results: Although not statistically significant, animals that received rTMS, apparently had better performance in passive avoidance task especially when applied after ischemia. The hypothermia demonstrated a significant efficiency, both in the histological analysis and in the passive avoidance task, associated or not to applications of rTMS and, in these animals undergoing ischemia during hypothermia, the ones who received rTMS had survival area in hippocampus significantly higher in histological analysis with hematoxylin and eosin. In animals undergone to ischemia during normal temperature, the rTMS has not shown to increase the area of hippocampal cell survival. Conclusions: rTMS (placebo or active, after or before the ischemia) seems to have a positive effect on passive avoidance task. The stimulation procedure appeared to be very traumatic and stressful for the animal, in which a few deaths occurred during the procedure, probably from asphyxiation due to restraint. The rTMS had a significant protective effect only in animals undergoing ischemia during hypothermia, as demonstrated in the histological analysis with hematoxylin and eosin

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