Dissertations / Theses on the topic 'DOPA'
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1
Khan, Ghulam Ahmed. "Enzymatic synthesis of L-DOPA esters." Thesis, University of Reading, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333598.
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Branden, Stansley. "L-dopa and the Serotonergic System." University of Toledo Health Science Campus / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1429543879.
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Wiese, Claudia Anette Elisabeth. "Metabolismus fluorierter DOPA-Isomere in aggregierenden Hirnzellkulturen /." [S.l.] : [s.n.], 1991. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=9542.
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Nelson, Michelle Amy. "Protein bound 3,4 dihydroxyphenyalanine as a signal for enhanced antioxidant defences /." full text via ADT, 2008. http://erl.canberra.edu.au/public/adt-AUC20081209.125208/index.html.
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Moheimen, Jamil. "Striatal neuropeptides associated with L- DOPA-induced dyskinesia." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-209915.
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Abstract Striatal neuropeptides associated with L-DOPA-induced dyskinesia 2012-02-14
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DIMOV, MICHEL. "Melanomes malins et 5-s-cysteinyl- dopa urinaire." Strasbourg 1, 1991. http://www.theses.fr/1991STR15033.
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Tison, François. "La L-Dopa endogène : aspects neurochimiques, physiologiques et étude anatomofonctionnelle par immunohistochimie dans le cerveau de rat." Bordeaux 2, 1990. http://www.theses.fr/1990BOR23037.
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Nelson, Michelle Amy, and n/a. "Protein Bound 3,4-Dihydroxyphenylalanine as a Signal for Enhanced Antioxidant Defences." University of Canberra. n/a, 2008. http://erl.canberra.edu.au./public/adt-AUC20081209.125208.
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Protein-bound 3,4-dihydroxyphenylalanine (PB-DOPA), a long-lived, redox-active product of
protein oxidation, is capable of functioning as both a pro- and anti-oxidant. A number of
in vitro and in vivo studies have demonstrated a toxic, non-toxic or even beneficial effect of
free DOPA, however little investigation has examined the physiological activity of PB-DOPA.
Furthermore, as free DOPA is currently the major treatment available for Parkinson?s disease,
most studies have focused on the effect of DOPA within neurological cells or tissues,
although the presence of PB-DOPA in other locations, for example within atherosclerotic
plaques, suggests that broader research is needed to fully understand the physiological effects
of both free and PB-DOPA.
The hypothesis presented in this thesis is that under physiological conditions, when little
redox active transition metal is available, PB-DOPA can function as a redox signalling
molecule, triggering an enhancement of cellular antioxidant defences, with a potentially
specific role in the regulation of defences targeted against protein oxidation. Physiological
levels of PB-DOPA are very low, however the level on individual proteins can change to a
proportionally large degree during oxidative stress, an appropriate property for a signalling
molecule. In addition, remarkably elevated levels occur in some pathologies, including
atherosclerosis. As an initial and commonly formed product of protein oxidation, PB-DOPA
is well placed for a signalling role, promoting a significant up-regulation of antioxidant
defences in the early stages of oxidative stress, before extensive damage has occurred. As an
initiator of antioxidant defences, PB-DOPA would be potentially useful as a therapeutic for
the treatment of diseases involving oxidative stress or the accumulation of oxidative damage.
The main objective of this thesis was, therefore, to examine the effect of PB-DOPA on the
cellular antioxidant defence system using monocytic and macrophage-like cells, key cells
involved in the formation of atherosclerotic plaques. The incorporation of free DOPA into
protein during protein synthesis, a process previously shown to occur both in vitro and in vivo,
was used to generate PB-DOPA. Neither free nor PB-DOPA were found to be toxic to
monocytic or macrophage-like cells in culture, but rather were both capable of protecting
these cells from oxidative stress. Free DOPA was shown to be capable of directly scavenging
radicals, a process that was thought to be in part responsible for the protection induced during
oxidative stress. The presence of free and PB-DOPA up-regulated the activity of catalase and
NAD(P)H:quinone oxidoreductase, two enzymatic antioxidants, however the activity of
superoxide dismutase and the concentration of oxidised and reduced glutathione were not
affected. Whilst it was thought that PB-DOPA would have a specific effect on the activity of
antioxidant defences targeted against protein oxidation, proteolysis and bulk chaperone
activity were not affected by a combination of free and PB-DOPA. Oxidatively-induced
protein aggregation, however, was inhibited by the presence of free and PB-DOPA,
suggesting that a more specific chaperone regulation may be taking place.
The regulation of gene and protein expression was thought to be one possible mechanism by
which PB-DOPA could function as a signalling molecule. To test this hypothesis, the effect of
free and PB-DOPA on transcription factor activation and protein expression were investigated.
Free and PB-DOPA did not induce the expression or activation of Nrf2, AP-1 or NFJB, three
transcription factors thought to be involved in the expressional regulation of genes involved in
the antioxidant defence system. However, the expression of a number of proteins, including
antioxidants, chaperones and proteins involved in cell cycle progression, were regulated in
monocytic and macrophage-like cells following the administration of free DOPA under
conditions that resulted in either a high or low level of PB-DOPA generation. The regulated
proteins differed between the two conditions, suggesting that the level of PB-DOPA may be a
key factor in determining the specific defences targeted.
The results presented in this thesis support the hypothesis that PB-DOPA can function as a
signalling molecule, triggering an enhancement of cellular antioxidant defences, with a
specific role in the regulation of the chaperone system, a key defence targeted against protein
oxidation. This thesis may provide the basis for the potential use of free or PB-DOPA as a
therapeutic for diseases known to involve oxidative stress or oxidative damage, however more
research will be required to determine if the effects demonstrated in this thesis are also
capable of occurring in vivo.
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Nevalainen, Nina, Martin Lundblad, Greg A. Gerhardt, and Ingrid Strömberg. "Striatal Glutamate Release in L-DOPA-Induced Dyskinetic Animals." Umeå universitet, Institutionen för strålningsvetenskaper, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-67595.
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L-DOPA-induced dyskinesia is a common side effect developed after chronic treatment with 3,4-dihydroxyphenyl-L-alanine (L-DOPA) in Parkinson's disease. The biological mechanisms behind this side effect are not fully comprehended although involvement of dopaminergic, serotonergic, and glutamatergic systems has been suggested. The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and L-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. Recordings were performed before and after local L-DOPA application in the striatum. In addition, effects from the 5-HT1A receptor agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OHDPAT; 1 mg/kg) was assessed on glutamate release and on dyskinetic behavior. The results revealed a bilateral similar to 30% reduction of basal extracellular glutamate concentration and attenuated potassium-evoked glutamate release after a unilateral dopamine-depletion in L-DOPA naive animals. In dyskinetic subjects, basal glutamate concentration was comparable to normal controls, although potassium-evoked glutamate release was reduced to similar levels as in drug naive dopamine-lesioned animals. Furthermore, acute striatal L-DOPA administration attenuated glutamate release in all groups, except in the dopamine-lesioned striatum of dyskinetic animals. Co-administration of 8-OHDPAT and L-DOPA decreased dyskinesia in dopamine-lesioned animals, but did not affect potassium-evoked glutamate release, which was seen in normal animals. These findings indicate altered glutamate transmission upon dopamine-depletion and dyskinesia.
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Cabral, Kibedi. "Towards optimisation of L-DOPA synthesis in Mucuna pruriens." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/70680/.
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This study examines the potential for increasing natural L-DOPA drug biosynthesis in Mucuna pruriens by silencing or “knocking down” expression of putative DOPA/tyrosine decarboxylase (Mp-ty/ddc) in situ. Mp-ty/ddc codes for DOPA/tyrosine decarboxylase (Mp-TY/DDC) which converts L-DOPA to dopamine in plants. The hypothesis of the work was that silencing the Mp-ty/ddc gene would result in accumulation of L-DOPA in the plant tissues. This work involved isolation and characterisation of 1.73 kb putative full-length ORF of Mp-ty/ddc. The gene showed 74% homology with TY/DDC protein alignments of other plants in the same taxa, although no enzyme activity was detected when the gene product was heterologously expressed. In addition, a protocol was developed for Agrobacterium mediated transformation of M. pruriens so as to be able to manipulate expression of the DOPA genes in situ. The cotyledonary nodal and hypocotyl tip explants regenerated shoots on M.S media supplemented with 50 μM BA, 0.5 μM NAA and 50 mg l-1 kanamycin selection also the nptII transgene was detected by PCR. The Agrobacteria strains GV3101 harbouring a pGREEN vector and carrying an Mp-ty/ddc antisense were used for the plant transformation experiments. Further work showed that the Mp-ty/ddc gene copy number was 1, the gene expression was highest in roots and stems, followed by seeds and was very low in leaves. On the other hand, L-DOPA-content in seeds was 17-fold higher relative to leaves and 15 fold relative to stems and roots.
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Edwards, Richard. "Synthesis of [18F]F-DOPA using hypervalent iodine compounds." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/84846/.
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[18F]F-DOPA is a widely used radiotracer most commonly employed in the diagnosis of Parkinson’s disease[1] and neuroendocrine tumours (NETs).[2] In this thesis, the syntheses of suitable diaryliodonium salt precursors for [18F]F-DOPA production via fluorination with nucleophilic, no carrier added (n.c.a.) [18F]fluoride are described. The complex iodonium salt precursors are prepared by a simple and robust procedure in good yields and are bench stable compounds. Incorporation of both ‘cold’ [19F]fluoride and ‘hot’ [18F]fluoride using the prepared precursors has been investigated.[3] Fluorinations occur with complete regioselectivity for fluorination at the DOPA moiety when using a range of precursors with varying protecting group strategies. Optimisation of the radiofluorination and subsequent isolation method allowed for isolation of a protected [18F]F-DOPA species in 2% radiochemical yield (RCY). Solid-Supported Iodonium Salts for Fluorinations (CH3) Secondly, solid-supported iodonium salt precursors have been prepared and used for the production of fluoroarenes. The importance of the resin functionality for the attachment of the iodonium salt moieties has been demonstrated. Use of a tris(aminoethyl) funtionalised resin rather than aminomethyl resin as starting material gives improved reproducibility and yields for precursor formation. The successful radiofluorination of a simple solid-supported precursor with no carrier added (n.c.a) [18F]fluoride is also reported, producing [18F]fluorobenzene with 3% radiochemical conversion (RCC).[4] Extension of the solid-supported methodology to the production of synthetically useful fluoroarenes was investigated. Preparation of benzyl protected 4-fluorophenol was accomplished using this strategy. Optimisation of the fluorination conditions gave 24% yield of the aryl fluoride from the resin bound iodonium salt precursor.
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Barnum, Christopher John. "The role of neuroinflammation in L-dopa-induced dyskinesia." Diss., Online access via UMI:, 2008.
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Marette, Caroline. "Approche de synthèses énantiosélectives automatisables de la 6-[18F] fluoro-L-Dopa et de la 3-O-méthyl-6-[18 Fluoro-L-Dopa." Toulouse 3, 2006. http://www.theses.fr/2006TOU30299.
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Aymard, Jean-Christophe. "Maladie de Parkinson : intérêt des formes retards de L Dopa." Paris 5, 1990. http://www.theses.fr/1990PA05P021.
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af, Bjerkén Sara. "On dopamine neurons : nerve fiber outgrowth and L-DOPA effects." Doctoral thesis, Umeå universitet, Integrativ medicinsk biologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1634.
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Parkinson’s disease is a disorder mainly characterized by progressive degeneration of dopamine producing neurons in the substantia nigra of the midbrain. The most commonly used treatment strategy is to pharmacologically restore the lost function by the administration of the dopaminergic precursor L-DOPA. Another treatment strategy is to replace the degenerated neurons with immature fetal ventral mesencephalic tissue, or ultimately stem cell-derived tissue. Grafting trials have, however, revealed poor reinnervation capacity of the grafts, leaving much of the striata dopamine-denervated. An additional drawback is the upcoming of dyskinesia (involuntary movements), a phenomenon also observed during L-DOPA treatment of Parkinson’s disease patients. Attempts to characterize nerve fiber formation from dopamine neurons have demonstrated that the nerve fibers are formed in two morphologically diverse outgrowth patterns, one early outgrowth seen in the absence of astrocytes and one later appearing outgrowth seen in co-existence with astrocytes. The overall objective of this thesis has been to study the dopaminergic outgrowth including guidance of nerve fiber formation, and to look into the mechanisms of L-DOPA-induced dyskinesia. The first paper in this thesis characterizes the different outgrowth patterns described above and their relation to different glial cells. The study demonstrated the two different outgrowth patterns to be a general phenomenon, applying not only to dopamine neurons. Attempts of characterization revealed no difference of origin in terms of dopaminergic subpopulations, i.e. A9 or A10, between the outgrowth patterns. Furthermore, the “roller-drum” technique was found optimal for studying the dual outgrowth sequences. The second and the third paper also utilized the “roller-drum” technique in order to promote both patterns of neuronal fiber formation. The effects of glial cell line-derived neurotrophic factor (GDNF) on the formation of dopamine nerve fibers, was investigated. Cultures prepared from gdnf knockout mice revealed that dopaminergic neurons survive and form nerve fiber outgrowth in the absence of GDNF. The dopaminergic nerve fibers exhibited an outgrowth pattern consistent with that previous observed in rat. GDNF was found to exert effect on the glial-associated outgrowth whereas the non-glial-associated was not affected. Astrocytic proliferation was inhibited using cytosine β-D-arabinofuranoside, resulting in reduced glial-associated outgrowth. The non-glial-associated dopaminergic outgrowth was on the other hand promoted, and was retained over longer time in culture. Furthermore, the non-glial-associated nerve fibers were found to target the fetal frontal cortex. Different developmental stages were shown to promote and affect the outgrowths differently. Taken together, these data indicate and state the importance of astrocytes and growth factors for neuronal nerve fiber formation and guidance. It also stresses the importance of fetal donor age at the time for transplantation. The fourth and fifth studies focus on L-DOPA dynamics and utilize in vivo chronoamperometry. In study four, 6-OHDA dopamine-depleted rats were exposed to chronic L-DOPA treatment and then rated as dyskinetic or non-dyskinetic. The electrochemical recordings demonstrated reduced KCl-evoked release in the intact striatum after chronic L-DOPA treatment. Time for maximal dopamine concentration after L-DOPA administration was found to be shorter in dyskinetic animals than in non-dyskinetic animals. The serotonergic nerve fiber content in the striatum was evaluated and brains from dyskinetic animals were found to exhibit significantly higher nerve fiber density compared to non-dyskinetic animals. Furthermore, the mechanisms behind the conversion of L-DOPA to dopamine in 6-OHDA dopamine-depleted rats were studied. Local administration of L-DOPA in the striatum increased the KCl-evoked dopamine release in the intact striatum. Acute application of L-DOPA resulted sometimes in a rapid conversion to dopamine, probably without vesicle packaging. This type of direct conversion is presumably occurring in non-neuronal tissue. Furthermore, KCl-evoked dopamine releases were present upon local application of L-DOPA in the dopamine-depleted striatum, suggesting that the conversion to dopamine took place elsewhere, than in dopaminergic nerve fibers. In conclusion, these studies state the importance of astrocytes for neuronal nerve fiber formation and elucidate the complexity of L-DOPA conversion in the brain.
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Lai, Chien-Tsai. "Oxidative stress and cytotoxicity induced by catecholamines and L-DOPA." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq23899.pdf.
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af, Bjerkén Sara. "On dopamine neurons : nerve fiber outgrowth and L-DOPA effects /." Umeå : Univ, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1634.
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Olofsson, Kristina. "Thiol-Ene CHemistry and Dopa-Functional Materials towards Biomedical Applications." Doctoral thesis, KTH, Ytbehandlingsteknik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-180716.
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Thiol-ene chemistry is versatile and efficient and can be used as a powerful tool in polymer synthesis. In this thesis, the concept of thiol-ene chemistry has been central, where it has been explored as a tool for the synthesis of well-defined hydrogels and dopa-functional materials towards biomedical applications; such as hydrogels, primers for adhesive fixation of bone fractures, self-healing gels, and micelles for drug-delivery. Using thiol-ene chemistry, well-defined hydrogels were realized in order to study how the structure influences properties such as swelling, stiffness and hydrolytic degradation. It was found that all these characteristics are related to each other, as a more loosely crosslinked hydrogel experiences higher swelling, lower stiffness and higher degradation rates. Dopa-functional materials have gained a lot of interest throughout the years due to the remarkable adhesive properties they possess in wet environments. In the pursuit of new primers towards thiol-ene functional crosslinked bone adhesives, compounds with dopa moieties were proposed. Primers derived from dopamine were found to enhance the adhesion towards bone, and it was concluded that addition of NaOH was essential to achieve good adhesion. The strongest adhesion was achieved when thiol and ene-functional primers were used in combination. Most synthetic routes to dopa-functional polymers involve several protection and deprotection steps and a more simplistic synthetic route is therefore desired. The possibility of using UV-initiated thiol-ene chemistry to produce dopa-functional polymers was therefore investigated. The resulting polymers were shown to exhibit self-healing properties upon complexation with Fe3+ ions. Finally, the developed synthetic route was used to produce dopa and allyl-functional triblock-co-polymers. These triblock-co-polymers were then used to form micelles and evaluated as drug-delivery vehicles for the cancer-drug doxorubicin. The micelles were found to have high drug-loading capacities and slow release profiles and showed promising results when evaluated against breast-cancer cells.Reaktioner mellan tioler och omättade kemiska föreningar utgör ett mångsidigt och effektivt redskap inom polymersyntes. I denna avhandling har begreppet tiol-en kemi varit centralt och kemin har använts för syntes av såväl väldefinierade hydrogeler som dopa-funktionella material. Dessa material har sedan utvärderats mot biomedicinska tillämpningar såsom hydrogeler, primers för fixering av benfrakturer, självläkande geler och kontrollerad läkemedelsleverans. Tiol-en-kemi har i denna avhandling använts för att framställa väldefinierade hydrogeler som sedan utvärderats med avseende på hur strukturen påverkar egenskaper såsom svällningsgrad, styvhet och nedbrytningshastighet. Det visade sig att alla dessa egenskaper är relaterade till varandra och att lösare tvärbundna hydrogeler uppvisar högre svällning, lägre styvhet och högre nedbrytningshastigheter. Marina musslor har en exceptionell förmåga att fästa mot olika ytor och på grund av detta har det visats en hel del intresse för dopa-funktionella material genom åren. På jakt efter en primer för att öka vidhäftningen hos benlim proponerades därför föreningar med dopafunktionella grupper. Det visade sig att dopaminderivat kunde förbättra vidhäftningen mot ben och det visade sig även att tillsats av natriumhydroxid var viktigt för att uppnå god vidhäftningsförmåga. Den starkaste vidhäftning uppnåddes när derivat med tiol och omättade bindningar användes i kombination. Syntes av dopafunktionella material involverar ofta flera reaktionssteg och en förenklad syntesväg är därför att eftersträva. UV-initierad tiol-en-kemi undersöktes därför som en möjlig syntesväg för att framställa dopafunktionella polymerer. Polymererna visade sig ha självläkande egenskaper vid komplexbildning med järnjoner. Slutligen användes denna syntesväg för att framställa blocksampolymerer. Dessa blocksampolymerer användes sedan för att bilda miceller med lovande resultat vid utvärdering för leverans av läkemedel mot bröstcancer.
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Prickett, Adam. "The epigenetics and role of Dopa Decarboxylase in heart development." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/the-epigenetics-and-role-of-dopa-decarboxylase-in-heart-development(fc53be8d-af43-4fac-9160-626ee8bf4f04).html.
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Genomic imprinting in mammals subjects a handful of genes to silencing on one allele depending on the parent-of-origin of that allele. The Ddc_exonla gene transcript is under the control of genomic imprinting in the developing and neonatal mouse heart with transcription occurring solely on the paternally inherited allele, with the maternally inherited allele epigenetically silenced. In all other tissues where Ddc_exonla is expressed transcription occurs from both parentally inherited alleles. CTCF plays a central role in controlling gene expression by regulating chromatin organisation, and has been shown to be fundamental for imprinting of the Igf2/H19 locus through its binding to the germline differentially methylated region (gDMR). This thesis explores the occurrence of CTCF binding both genome-wide and at imprinting gDMRs in mouse brain in order to assess its relevance to the control of transcription in vivo. 49,358 significant binding sites are detected across the genome and binding is enriched at gene coding regions but depleted at distal intergenic regions. 12/20 (60%) imprinted gDMRs are bound by CTCF, of these five bind in a parent-of-origin specific manner implicating CTCF in the control of a subset of imprinted genes including Ddc_exonla. Comparative analysis of CTCF binding in multiple tissues shows a high degree of overlap, and Motif analysis reveals CTCF binds the same canonical motif sequence in each tissue. CTCF binding in the absence of the canonical motif is more tissue-specific. Ddc_exonla expression is imprinted in the developing heart but is bi-allelic in brain, and the mechanism of imprinting is not known. To explore a model for imprinting control the epigenetic profile of the Ode imprinted locus was examined in detail. Methylation analysis reveals several regions that are differentially methylated between heart and brain. One region constitutes a CpG rich region at the promoter of GrblO, another imprinted gene located adjacent to Ddc_exonla. The second region is at the promoter of AK0066690, a non-coding antisense transcript which initiates in intron four of Ddc_exonla. CTCF binding at the Ddc/GrblO locus is assayed in heart and brain, and binding is invariant between tissue types. The AK0066690 transcript is expressed in the neonatal mouse heart but not in the neonatal brain, consistent with a model of silencing Ddc_exonla on the maternal allele via transcriptional interference. Ddc_exonla codes for the Dopa Decarboxylase (Ddc) protein, which is predominately expressed in the developing myocardium, this points to a role in fetal heart development. The role of Ddc in cardiogenesis is explored using knockout mice lacking Ddc_exonla expression in heart. Expression microarrays were used to detect changes in gene expression, and morphometric analysis using 3D imaging was performed to look for gross morphological changes. Results suggest that Ddc plays a role in regulating cellular proliferation and cardiogenesis of the developing myocardium as mice lacking Ddc show a significant thinning of the apical portion of the right ventricle, a region that shows abundant Ddc expression. In this thesis the significance of CTCF binding to imprinting control is examined and the observations applied in a locus specific manner to explore both the mechanistic control, and the functional role of Ddc in the developing mouse heart.
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Ko, Daniel. "RGS proteins in experimental Parkinsonism and L-DOPA-induced dyskinesia." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/rgs-proteins-in-experimental-parkinsonism-and-ldopainduced-dyskinesia(97c4a365-d9d5-48fb-8ccd-9c653b801427).html.
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder producing a clinical syndrome of bradykinesia, rigidity and resting tremor. These motor symptoms appear due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and loss of dopamine in the striatum, which subsequently leads to an imbalance of the basal ganglia motor circuit. The most effective pharmacological treatment for PD is L-3,4-dihydroxyphenylalanine (L-DOPA), the immediate metabolic precursor of dopamine, which effectively restores motor function. L-DOPA is catabolised into dopamine and replaces neurotransmitter loss in PD. However, long-term L-DOPA treatment leads to abnormal involuntary movements (AIMs), such as L-DOPA-induced dyskinesia (LID), which reduces the quality of life in PD patients. Currently, there are no reliable pharmacological treatments for these motor complications. Clinical and preclinical studies have shown that development and expression of LID is linked to unregulated dopamine release and plasticity-induced changes of striatal dopaminergic and non-dopaminergic signalling pathways. The activities of these pathways can be modulated by neurotransmitter receptors of a specific classification, the G-protein-coupled receptor (GPCR) family. In turn, GPCRs are regulated by certain endogenous proteins, the regulators of G-protein signalling (RGS) proteins. Numerous RGS protein subtypes are expressed in the striatum but their roles in PD and LID remain poorly understood. Given the modulatory function of RGS proteins in the striatum, these endogenous factors may have pathophysiological roles in the expression of motor symptoms in PD and LID. The studies presented in this thesis investigated the roles of RGS proteins in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and LID. Rats received unilateral 6-OHDA lesions of the right medial forebrain bundle to induce severe dopamine denervation. L-DOPA/benserazide (6/15 mg/kg) was then administered once daily for at least 21 days to induce stable abnormal involuntary movements (AIMs). In Chapter 2 of this thesis, increased levels of RGS2 and RGS4 mRNA were found in the rostral striatum of the unilateral 6-OHDA-lesioned rat model of LID. Moreover, elevated levels of RGS4 mRNA were specific to sensorimotor regions and positively correlated with AIMs severity. These molecular and behavioural data suggest that RGS4 proteins are involved in the expression of LID. In Chapters 3 and 4, behavioural studies conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that acute inhibition of striatal RGS4 proteins reduced the expression of AIMs and improved overall motor function. Moreover, repeated de novo treatment with RGS4 protein inhibitors, in combination with L-DOPA, attenuated the development of AIMs and reduced the overexpression of preproenkephalin-B, a molecular marker of LID. These behavioural and molecular data suggest that blockade of RGS4 proteins can reduce the induction of LID. In Chapter 5, in vivo microdialysis conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that systemic administration of RGS4 protein inhibitors, in combination with L-DOPA, attenuated unregulated striatal dopamine efflux. These data suggest that RGS4 proteins may regulate specific G-protein coupled receptors, such as 5-HT1A receptors, that modulate striatal dopamine release. In conclusion, the work presented in this thesis shows that RGS4 proteins play a pathophysiological role in the expression and development of LID. These proteins could mediate regulation of key neurotransmitter receptors involved in LID, making them a potential therapeutic target for the development of future treatments.
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Wynne, Martin F. "Peptidyl DOPA biochemistry and immunobiology in the protochordate Pyura stolonifera /." St. Lucia, Qld, 2000. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16370.pdf.
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Nevalainen, Nina. "Dysfunction in the nigrostriatal system : effects of L-DOPA and GDNF." Doctoral thesis, Umeå universitet, Histologi med cellbiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-64149.
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Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID.
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Lefebvre, Marie Julie Christine. "The quantification of L-dopa induced dyskinesia in Parkinson's disease patients." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27701.
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Parkinson's disease (PD) patients experience postural instability as a primary motor symptom (Parkinson, 1817). The majority of PD patients use L-dopa to treat motor symptoms associated with the disease; however, extended use of L-dopa can cause involuntary movement production termed L-dopa induced dyskinesia (LID) (Bezard et al., 2001). Recently, researchers have speculated that postural sway variability (CoP variability) is associated with clinically unapparent LID (Rocchi et al., 2004). This experiment sought to determine the relationship between CoP variability and LID in PD patients. Eight PD patients on L-dopa medication and eight age matched neurologically healthy control subjects performed a precision aiming task where we manipulated the orientation, size and distance of the target. We recorded CoP fluctuations using two force plates and kinematics of the head, torso, arm and leg segments using the VICON 3-D motion capture system. The results indicate that decreased joint coordination of the head, arm and torso segments contribute to greater CoP variability in PD patients, particularly in the ML direction. Our results also reveal that increased task difficulty by manipulation of target distance increases movement amplitude, and consequently CoP variability. These findings suggest a causal relationship between LID and CoP variability in PD patients.
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Stevenson, James. "Manual tracking in Parkinson's disease : implications for L-dopa-induced dyskinesias." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/34934.
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Though Parkinson’s disease (PD) is considered to be a prototypical basal ganglia disorder, it has become increasingly clear that this traditional view does not capture the complexity of the disease pathophysiology. For instance, imaging studies demonstrate altered cerebellar activity in PD that may compensate for and/or contribute to the symptoms of the disease. L-dopa-induced dyskinesias (LID) are involuntary writhing movements that commonly occur as a side effect of L-dopa therapy, and despite the prevalence of LID their underlying mechanisms are poorly understood. Altered cerebellar activity in PD may contribute to the pathophysiology of LID, and due to altered ‘forward models’ lead dyskinetic subjects to more heavily rely on ambiguous visual feedback.
The principal aim of this thesis was to investigate the ability of PD subjects to de-weight ambiguous visual feedback during motor performance, while examining this ability as well as subtle differences in motor performance across dyskinetic and non-dyskinetic PD subjects. To this end we designed a large-amplitude visually guided tracking task where the target ‘jittered’ about the desired trajectory, and used root mean square (RMS) error and linear dynamical system (LDS) models to quantify tracking performance. The three major findings of this work were: 1) in addition to their known susceptibility to speed, PD subjects off medication were significantly more susceptible to increasing visual uncertainty than control subjects, 2) despite similar RMS error during non-ambiguous tracking the damping ratio parameter of the LDS models was significantly lower for dyskinetic subjects off medication, and 3) dyskinetic PD subjects were significantly more susceptible to visual uncertainty than non-dyskinetic and control subjects, and though L-dopa improved their overall tracking ability, this came at the price of a greater response to and reliance on ambiguous visual feedback.
From this work we conclude that PD subjects demonstrate an impaired ability to de-weight ambiguous visual input, possibly due to inadequate forward models, and which may be specific to LID pathophysiology. The presence of motor abnormalities while dyskinetic subjects are off medication and not actively experiencing LID is suggestive of persistent neural plasticity. We argue these findings are related to altered cerebellar function in PD.
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Perera, Aruna B. Kane Robert R. "Modification of fresh tissue surfaces ; synthesis of labeled L-dopa analogs; and synthesis of metoclopramide analogs /." Waco, Tex. : Baylor University, 2005. http://hdl.handle.net/2104/2998.
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GOZLAN, DIDIER. "Evolution des parkinsoniens traites par dopatherapie : a propos de 25 cas." Limoges, 1988. http://www.theses.fr/1988LIMO0203.
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Fischer, Diana Gabriela. "Dopa-responsive Dystonie molekulargenetische Untersuchungen am Guanosintriphosphat-Cyclohydrolase-I- und TorsinA-Gen /." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=965417115.
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Balci, Meral. "Periodische Beinbewegungen beim Obstruktiven Schlafapnoesyndrom: Einfluss der CPAP-Therapie + L-Dopa-Medikation." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974509620.
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Aljabri, Hareb Mohammed. "Comparative analysis of Anopheles gambiae L-tyrosine decarboxylase and L-DOPA decarboxylase." Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/34788.
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A major pathway of tyramine and dopamine synthesis in insects is through the decarboxylation of tyrosine and DOPA, respectively. Although tyrosine decarboxylase (TDC) has been mentioned in some reports, it has never been critically analyzed. The high sequence identity shared by tyrosine decarboxylase and DOPA decarboxylase in insects, and the similar structures of the substrates, tyrosine and DOPA, raise the possibility that both tyrosine decarboxylase and DOPA decarboxylase (DDC) have activities to tyrosine and DOPA. In this study, after tyrosine decarboxylase and DOPA decarboxylase enzymes of Anopheles gambiae were expressed, their substrate specificities and biochemical properties were critically analyzed. My results provide clear biochemical evidence establishing that the mosquito tyrosine decarboxylase functions primarily on the production of tyramine with low activity to DOPA. In contrast, mosquito DOPA decarboxylase is highly specific to DOPA with essentially no activity to tyrosine.Master of Science in Life Sciences
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BRIQUE, SERGE. "Dystonie dopa-sensible : donnees cliniques et biochimiques a propos d'une nouvelle famille." Lille 2, 1994. http://www.theses.fr/1994LIL2M274.
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Bruneau, Gilles. "Études structurales et localisations chromosomiques des gènes de la L-DOPA décarboxylase de rat et de l'histidine décarboxylase humaine." Paris 12, 1993. http://www.theses.fr/1993PA120022.
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La dopa decarboxylase et l'histidine decarboxylase appartiennent a une famille d'enzymes de decarboxylation phylogenetiquement reliees et utilisant le phosphate de pyridoxal comme cofacteur. Le gene de la ddc de rat possede deux promoteurs dont l'expression tissu-specifique conduit a la formation de deux arnm differant par leurs extremites 5 non codantes. Les deux regions promotrices possedent une boite tata et un seul site d'initiation de la transcription. Aucune ne presente les caracteristiques des promoteurs de genes housekeeping. Les organisations structurales des genes ddc de l'homme et du rat sont similaires. L'etude de l'organisation intron/exon de la region 5 du gene de l'hdc permet de montrer que certaines des positions de sites d'epissage des genes de ddc et d'hdc de mammiferes, sont identiques sur un alignement des sequences de leurs arnm. L'ancetre commun aux genes des deux enzymes, dont la duplication est anterieure a la divergence vertebres/invertebres, devait posseder ces sites. Ceux-ci ont vraisemblablement disparu au cours de l'evolution de la drosophile. Le gene de la ddc a ete localise sur les chromosomes 7, 11 et 14 de l'homme, de la souris et du rat, respectivement. Le gene de l'hdc humaine est situe sur le chromosome 15
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Göldner, Alexander. "Therapeutische Wirksamkeit von L-Dopa bei Amyotropher Lateralsklerose - eine Analyse von 50 therapeutischen Heilversuchen." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-65195.
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Lira, Sonja. "Therapeutische Wirksamkeit von L-Dopa bei Amyotropher Lateralsklerose - eine Beobachtung von 39 Patienten im Langzeitverlauf." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-65969.
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Holiga, Štefan. "Personalizing functional Magnetic Resonance Protocols for Studying Neural Substrates of Motor Deficits in Parkinson’s Disease." Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-124904.
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Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized by a large number of motor and non-motor deficits, which significantly contribute to reduced quality of life. Despite the definition of the broad spectrum of clinical characteristics, mechanisms triggering illness, the nature of its progression and a character of therapeutic effects still remain unknown. The enormous advances in magnetic resonance imaging (MRI) in the last decades have significantly affected the research attempts to uncover the functional and structural abnormalities in PD and have helped to develop and monitor various treatment strategies, of which dopamine replacement strategies, mainly in form of levodopa, has been the gold standard since the late seventies and eighties. Motor, task-related functional MRI (fMRI) has been extensively used to assess the pathological state of the motor circuitry in PD. Several studies employed motor paradigms and fMRI to review the functional brain responses of participants to levodopa treatment. Interestingly, they provided conflicting results. Wide spectrum of symptoms, variability and asymmetry of the disease presentation, several treatment approaches and their divergent outcomes make PD enormously heterogeneous. In this work we hypothesized that not considering the disease heterogeneity might have been an adequate cause for the discrepant results in aforementioned studies. We show that not accounting for the disease variability might indeed compromise the results and invalidate the consequent interpretations. Accordingly, we propose and formalize a statistical approach to account for the intra and inter subject variability. This might help to minimize this bias in future motor fMRI studies revealing the functional brain dysfunction and contribute to the understanding of still unknown pathophysiological mechanisms underlying PD.
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Simmons, Donald Karl. "L-DOPA production in a liquid membrane enzyme reactor: process development and modeling." Diss., Georgia Institute of Technology, 1990. http://hdl.handle.net/1853/10120.
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Riahi, Golnasim. "Implication of the serotoninergic systems in Parkinson's disease and L-Dopa-induced dyskinesia." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/28974/28974.pdf.
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Malerbi, Marion. "Rôle de Narp dans le développement des dyskinésies induites par la L-DOPA." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066025/document.
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Le traitement substitutif par la L-DOPA, indiqué dans la maladie de Parkinson, induit à terme des complications motrices appelées les dyskinésies induites par la L-DOPA. L'apparition des dyskinésies est due, au moins en partie, à la mise en place d'une plasticité aberrante dans le striatum, qui fait suite à des modifications transcriptionnelles induites par la L-DOPA. Une analyse du transcriptome nous a permis d'identifier le gène Nptx2, codant pour la neuropentraxine Narp, comme étant un candidat potentiellement impliqué dans l'apparition des dyskinésies. L'objectif de ce travail était d'étudier la régulation et le rôle de Narp dans l'apparition des dyskinésies, dans un modèle de souris lésée à la 6-hydroxydopamine. Nous avons montré que les dyskinésies induites par la L-DOPA sont diminuées chez des souris invalidées pour Nptx2 (Narp-KO). Par ailleurs, l'injection dans le striatum dorsal d'un adénovirus exprimant une forme dominante négative de Narp, induit une réduction importante des scores de dyskinésies. Dans le striatum, Narp est exprimé par les neurones épineux de taille moyenne et par les interneurones à parvalbumine. Après une stimulation dopaminergique, l'augmentation de l'expression de Nptx2 s'accompagne d'un enrichissement de Narp au niveau synaptique. Nos travaux montrent donc que Narp joue un rôle important dans le développement des dyskinésies et suggèrent qu'il pourrait être impliqué dans la plasticité synaptique des neurones du striatum, comme cela a été montré dans l'hippocampe. Ces résultats permettent d'ouvrir de nouvelles perspectives thérapeutiques pour retarder l'apparition de ces complications motrices chez les patients parkinsoniensDopaminergic replacement therapy in Parkinson’s disease is hampered by the occurrence of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID result from L-DOPA-induced aberrant plasticity in the striatum due to modifications of the transcriptional program. Using a microarray-based approach, we identified Narp as a putative candidate implicated in LID induction. Thus, we investigated Narp involvement in LID by examining abnormal involuntary movements (AIM) development in Narp genetically-ablated mice or upon intrastriatal injection of a dominant negative form of Narp. Interestingly, the total AIM score was greatly reduced in these two models of impaired Narp expression. Hence, my results highlight Narp as an important actor in LID development. Then, I further examined Narp regulatory mechanisms in the striatum and I demonstrated that dopamine stimulation leads to increased Narp expression both at the transcriptional level and at the protein level through its accumulation within the synaptic compartment. These findings advance knowledge about mechanisms underlying dyskinesia with the hope of delaying their appearance in patients
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Fuhrer, Hannah [Verfasser]. "Die Auswirkungen von L-Dopa auf nicht-deklarative und deklarative Gedächtnisprozesse / Hannah Fuhrer." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1068209194/34.
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Militza, Monteverde. "det är inte hud, det är puder : dopa min kropp vs. dopamin-kropp." Thesis, Kungl. Konsthögskolan, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kkh:diva-215.
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ska jag springa runt i 3D-labbet för att tänka på hur leder fungerar, en animerad figur som inte får röra sig som en robot, min dröm är att hitta den där parfymen som luktar plastdocka lika mycket som jag tänker ge min pojkvän parfymen som luktar nytryckt bok, det börjar med Fountain of Youth och slutar i syntetisk biologi och DNA-mutation, – allt för att hålla sig vid liv, eller åtminstone ge intryck av att göra så
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BOI, LAURA. "Neuroinflammation in Parkinson’s Disease: role in neuropathology and L-DOPA-induced motor complications." Doctoral thesis, Università degli Studi di Cagliari, 2020. http://hdl.handle.net/11584/284805.
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Parkinson Disease (PD) is a neurodegenerative disorder characterized by the progressive dopaminergic loss in the Substantia Nigra (SN) and the presence of intracellular Lewy Bodies (LB) containing deposits of the protein α-synuclein (α-syn). Several studies identified the neuroinflammatory processes as important factors in the neuropathology of PD, involving mainly microglia cells. Indeed, in PD microglia lose their ability to autoregulate, sustaining a chronic pro-inflammatory environment in dopaminergic areas which exacerbates the neurodegenerative process. Moreover, recent pre-clinical studies have suggested a role of neuroinflammation in the pathophysiology of L-DOPA-induced dyskinesia, showing that the chronic administration of L-DOPA exacerbates the pre-existing inflammatory environment which may contribute to the altered neurotransmission associated with dyskinesia.
The main component of LB is α-synuclein in its fibrillar form, but recent evidence suggests that the most toxic strain of α-synuclein are small soluble α-synuclein oligomers. Moreover, structure-based features have been suggested to mediate the toxicity of highly toxic α-synuclein oligomers. While the central role of α-synuclein in PD is generally acknowledged, the mechanisms underlying the neurotoxicity of α-synuclein oligomers, and their pathological interaction with Central Nervous System (CNS) immune-cells within PD-related neuroinflammation is still largely unknown.
In the first part of our project (part I), we tested the neurotoxicity in vivo of α-synuclein oligomers previously recognized to hold a structure that confers high toxicity in in vitro models, and we focused on the inflammatory response elicited by these toxic α-synuclein oligomers and on their interaction with microglial cells.
Thereafter, in the second part of our project (part II) we addressed the role of neuroinflammation in L-DOPA-induced dyskinesia. L-DOPA therapy is the gold standard for PD, however long-term administration leads to the onset of L-DOPA-induced abnormal involuntary movements named dyskinesia. Recent studies have suggested that neuroinflammatory processes play a pivotal role in dyskinesia, and the proinflammatory cytokine Tumor Necrosis Factor (TNF)-α may be a key player being also involved in synaptic strength mechanisms and in angiogenesis, another important component in the neuropathology of L-DOPA-induced dyskinesia (LID). Here, we tested whether the immunomodulatory drugs thalidomide (TLD) and its more potent derivative 3,6-dithiothalidomide (DTT), which specifically inhibit the synthesis of TNF-α, were effective in alleviating the L-DOPA-induced dyskinetic outcome in a rat model of PD.
Oligomer infusion caused a gradual development of PD neuropathology. Microgliosis and increased levels of inflammatory cytokines were measured one month after oligomers-infusion, without any evidence of neurodegeneration and behavioral deficits. Notably, three months after the injection, rats displayed motor impairment, associated with 40% loss of dopaminergic neurons in the oligomers-treated SN, reaching a 50% cell loss after five months. Dopamine levels were significantly reduced by 40% in the striatum homolateral to α-synuclein infusion. An intense inflammatory response with reactive microglia and high levels of TNF-α immunoreactivity were detected in SNpc. Large deposits of p-αsyn were found within microglial cells three and five months post-infusion.
TLD and DTT significantly reduced the severity of AIMs while not affecting the contralateral turning. Both drugs inhibited the L-DOPA-induced microgliosis and excessive TNF-α in the Str and SNpr, while restoring control levels of the anti-inflammatory cytokine interleukine (IL)-10 at striatal level. DTT inhibited L-DOPA-induced angiogenesis in SNpr and Str. GLUR1 analysis revealed that L-DOPA-induced an overexpression of this GLUR1 subunit in the Str, that was restored to normal levels by DTT.
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Oueslati, Abid. "Implication des systèmes à acides aminés excitateurs dans la maladie de Parkinson et ses traitements." Aix-Marseille 2, 2008. http://theses.univ-amu.fr.lama.univ-amu.fr/2008AIX22015.pdf.
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L’expression des symptômes moteurs de la maladie de Parkinson (MP) est associée à une activation anormale des systèmes glutamatergiques dans les ganglions de la base (GB), incluant le noyau subthalamique (NST). De fait, le traitement chirurgical de la MP par stimulation à haute fréquence (SHF) du NST s’est imposé au cours de ces dernières années comme une option thérapeutique de choix pour les patients à des stades avancés de la maladie chez lesquels le traitement de référence à la L-DOPA induit à long terme des effets indésirables sévères. Cependant, les bases cellulaires de ses effets thérapeutiques restent méconnues et son application présente des limitations importantes. Dans la recherche de traitements pharmacologiques alternatifs, les récepteurs métabotropiques du glutamate (mGluRs) ont été identifiés comme des cibles moléculaires d’intérêt. Dans ce contexte, le premier objectif de mes travaux de thèse a été d’analyser l’impact de la SHF du NST appliquée de façon prolongée sur le fonctionnement physiopathologique des GB et de caractériser son interaction avec les effets de la LDOPA dans un modèle des stades tardifs de la MP, chez le rat. Nous avons montré que 5 jours de SHF continue du NST sont nécessaires pour corriger les déficits akinétiques induits par la lésion dopaminergique extensive et normaliser l’activité métabolique neuronale au niveau du cortex moteur. De plus, nous avons identifié le striatum comme un site majeur d’interaction entre les deux traitements. En effet, l’association de la SHF prolongée du NST avec un traitement chronique à la L-DOPA potentialise les dyskinésies DOPA-induites ainsi que les réponses cellulaires striatales qui leur sont associées. Ce travail montre que la SHF du NST n’a pas d’effet anti-dyskinétique direct et suggère que la SHF du NST agisse principalement au niveau du striatum au travers d’une voie de signalisation activée par la L-DOPA. Dans le deuxième axe, nous avons caractérisé les substrats cellulaires des effets bénéfiques du blocage pharmacologique du sous-type 5 des mGluRs (mGluR5), par un antagoniste sélectif, le MPEP, dans un modèle des stades symptomatiques précoces de la MP, chez le rat. Nos résultats montrent que, contrairement aux effets extensifs de la lésion dopaminergique totale, la lésion partielle a des effets focalisés dans le réseau des GB : une augmentation de l’activité métabolique neuronale dans le NST et la SNr, associés une hypoactivité du cortex moteur. L’effet anti-akinétique du traitement au MPEP est corrélé à la normalisation de l’activité neuronale dans ces structures. Ces données, montrent l’implication majeure d’un sous-circuit subthalamo-nigro-cortical dans l’expression de l’akinésie dans les stades précoces de la MP et soulignent le potentiel thérapeutique du blocage des mGluR5. L’ensemble de ce travail représente une contribution à l’avancée des connaissances sur les bases neurales et moléculaires des symptômes parkinsoniens et de l’action de différents traitements ciblant les systèmes glutamatergiques sur le contrôle moteur, avec des retombées potentielles pour améliorer le traitement symptomatique de la MPThe abnormal activation of glutamate systems, notably subthalamic nucleus (STN), in response to dopamine denervation in the basal ganglia (BG), plays a major role in the expression of the symptoms of Parkinson’s disease (PD). The surgical treatment by high frequency stimulation (HFS) of STN has emerged as an efficient therapeutic option for PD patients suffering from severe side effects produced by long-term L-DOPA treatment. However, the action mechanisms of this stimulation remain poorly understood and its application presents important limitations. In the research of alternative pharmacological treatment, metabotropic glutamate receptors (mGluRs) have been recently stressed as interesting molecular targets. In this context, the first objective of my PhD work was to characterize the neural bases of the therapeutic action of STN HFS and its interaction with L-DOPA medication in a rat model of late PD. Our results show that prolonged STN HFS for several days is required to significantly alleviate the severe akinetic deficits produced by extensive dopamine lesion. Such prolonged HFS did not alleviate but even exacerbated the L-DOPA-induced dyskinesias (LID). We further identified striatum as a main site for the interactions between the two treatments. Indeed, when applied together or after chronic dyskinesiogenic L-DOPA treatment, the surgical treatment potentiated the L-DOPA-mediated cellular responses, including those linked to LID. These data argue against a direct anti-dyskinetic action of STN-HFS and suggest that this surgical treatment acts primarily at striatal level through L-DOPA signalling pathway. The second objective was to identify the cellular substrates of the antiparkinsonian benefits provided by the pharmacological blockade of mGluR5 using the antagonist MPEP in a rat model of early symptomatic stages of PD based on restricted denervation of the motor striatal territory. In this model, the expression of akinetic deficits was associated with focused metabolic changes in the corticobasal ganglia-cortical loop: neuronal metabolic activity was increased in the STN and SNr and decreased in the frontal cortex. The anti-akinetic action of MPEP was correlated with the reversal of these lesion-induced cellular changes. These data point to the major role of a subthalamo-nigro-cortical sub-circuit in the expression of akinesia in early PD stages, and to mGluR5 negative modulation as a promising antiparkinsonian strategy. Overall, this work contributes in advancing our knowledge of the neural and cellular bases of PD symptoms and of the action of different treatments targeting glutamate systems on motor control, with potential insights onto the symptomatic treatment of PD
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DUMAS, MYRIAM. "Les problemes bucco-dentaires chez le parkinsonien." Lyon 1, 1987. http://www.theses.fr/1987LYO1A021.
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Ma, Bonita. "Augmentation of L-DOPA-evoked dopamine efflux by Methylphenidate : role for the D2 autoreceptor?" Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50926.
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Using a 6-OHDA model of Parkinson’s disease, we have preliminary evidence that L-DOPA-derived dopamine (DA) ceases to be released through conventional mechanisms of exocytosis under severe denervation. This may be problematic, as large, and possibly unregulated release of L-DOPA-derived DA would be expected to cause abnormal patterns of DA stimulation at the postsynaptic receptors, likely contributing to the development of dyskinesia.
This issue may be overcome with the Dopamine Transporter (DAT) blocker Methylphenidate (MPD). Ahn and Phillips observed that MPD augmented the L-DOPA-derived DA efflux in a manner consistent with the under-appreciated fact that MPD also acts as a vesicular monoamine transporter (VMAT2) agonist (Volz, 2008), thereby facilitating the sequestration of cytosolic DA into vesicles, where it could enter into a cycle of impulse-dependent release processes. The hypothesis that MPD may influence the sequestration and release of L-DOPA-derived DA into presynaptically-regulated mechanisms of exocytosis may have beneficial therapeutic implications.
Thus, the two major objectives of this thesis were first to assess whether L-DOPA-derived DA remained under presynaptic D2 autoreceptor regulation dependent on the severity of striatal denervation, and second, to investigate the mechanism(s) by which MPD may facilitate vesicular DA release, possibly by involvement of the D2 autoreceptor. L-DOPA was reverse-dialyzed into the intact and 6-OHDA lesioned dorsal striatum of the rat, followed by the reverse-dialysis of the D2 autoreceptor agonist and antagonist, Quinpirole and Eticlopride, or the VMAT2 inhibitor, Tetrabenazine. Although L-DOPA-evoked DA efflux remained under D2 autoreceptor control in the intact and moderately lesioned striatum, in the case of severe, 95% denervation, L-DOPA-evoked DA efflux was unaffected by D2 autoreceptor regulation or VMAT2 inhibition. However, despite the apparent loss of autoreceptor regulation, a subsequent study found that inhibitory binding of the D2 autoreceptor by reverse-dialysis of Eticlopride into the severely denervated striatum prior to the administration of MPD, completely blocked MPD-induced augmentation of L-DOPA-derived DA.
These results implicate the D2 autoreceptor in a novel mechanism by which MPD can facilitate DA neurotransmission, and suggest that even under conditions of severe denervation, the presynaptic D2 autoreceptor may be manipulated pharmacologically to facilitate the exocytotic release of L-DOPA-derived DA.Medicine, Faculty of
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Challapa, Velásquez Nancy Mariela. "Fisicoquímica del neurotransmisor dopamina y su precursor L-DOPA utilizando métodos teóricos y experimentales." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2018. https://hdl.handle.net/20.500.12672/8026.
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Publicación a texto completo no autorizada por el autorEstudia las propiedades de estabilidad termodinámica y reactividad por transferencia protónica intrínsecas (en fase gas) del neurotransmisor dopamina y su precursor L-DOPA. Para ello hace uso de la Metodología DFT (B3LYP) y “ab-initio” (métodos G3 y G4) para el estudio conformacional en especies neutras, protonadas y desprotonadas, en fase gaseosa; y la determinación experimental, mediante espectrometría de masas de triple-cuadrupolo con fuente ESI (electrospray), de la afinidad protónica y basicidad de la Dopamina y acidez de la L-DOPA en fase gaseosa, aplicando el Método Cinético Extendido de Cooks (EKCM).
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Charbonnier-Beaupel, Fanny. "Mécanismes moléculaires des dyskinésies induites par la l-dopa dans la maladie de parkinson." Paris 6, 2013. http://www.theses.fr/2013PA066582.
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Dans la maladie de Parkinson, le traitement par la L-DOPA est associé à l’apparition des dyskinésies (LID). Une des hypothèses majeures est qu’elles résultent de l’induction d’un programme transcriptionnel aberrant dans les neurones striataux via l’hypersensibilisation des récepteurs D1 et l’activation de ERK. Pour identifier les gènes induits par la L-DOPA, dépendants de ERK et associés au développement des LID, nous avons effectué des analyses du transcriptome dans le striatum de souris lésées à la 6-hydroxydopamine. Tout d’abord, des souris ont été sacrifiées 0, 1, 3 et 6 h après la L-DOPA. Puis, des souris ont été traitées avec le SL327, inhibiteur de MEK, ou un véhicule avant la L-DOPA. Enfin, nous avons comparé l'expression génique chez les souris hautement et faiblement dyskinétiques après traitement par la L-DOPA. La première expérience a identifié 709 gènes dérégulés par la L-DOPA. L'analyse ontologique a suggéré une rétroaction négative sur la cascade d'activation de ERK. Dans les expériences suivantes, la dérégulation de 28 gènes a été bloquée par le SL327 et 26 gènes ont été retrouvés différentiellement régulés chez les animaux hautement et faiblement dyskinétiques. L'intersection de ces listes a identifié 5 gènes : Nptx2, Nedd4l, FosB, Th et Ccrn4l. Enfin, en utilisant un protocole d'escalade de dose, on a observé une diminution du développement des LID chez les souris Nptx2 KO. En conclusion, nous avons identifié une signature moléculaire induite par le traitement par la L-DOPA dans le striatum dénervé, dépendante de ERK et associée au développement précoce des LID. Et nous avons démontré l'implication d'un de ces gènes, Nptx2, dans le développement des LIDIn Parkinson’s disease, the long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons through sensitized D1 dopamine receptors, and the activation of the extracellular signal-regulated kinase (ERK). To identify genes induced by L-DOPA, dependent on ERK, and associated with LID, we performed transcriptome analyses in the striatum of 6-hydroxydopaminelesioned mice. A first group of mice was sacrificed 0, 1, 3 and 6 h after L-DOPA. In a second experiment, mice were treated with the MEK inhibitor SL327 or vehicle prior to L-DOPA. In a third experiment, we compared gene expression in highly and weakly dyskinetic mice after a subchronic treatment with L-DOPA. The first experiment identified 709 probes deregulated by L-DOPA. The gene ontology analysis suggested a rapid onset of a negative feedback on ERK activation cascade by L-DOPA in the striatum. In subsequent microarray experiments, the L-DOPA-induced deregulation of 28 genes was blocked by SL327, and 26 genes were differentially expressed in highly and weakly dyskinetic animals. The intersection of the gene lists identified five genes: Nptx2, Nedd4l, FosB, Th, and Ccrn4l. Nptx2 was further explored. By using an escalating dose protocol, we observed a decreased L-DOPA induced dyskinesia development in Narp knockout mice. In conclusion, we identified a molecular signature induced in the dopamine-denervated striatum by L-DOPA, dependent on ERK and associated with LID development. We demonstrated the implication of one of these genes, Nptx2, in the development of LID
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BOREK, MICHAEL. "Pharmacocinetique de la l-dopa et de la 3-o methyldopa chez des parkinsoniens fluctuants et non fluctuants et determination des taux plasmatiques de dopa en phaseon et off : etude retrospective sur 55 cas." Lyon 1, 1992. http://www.theses.fr/1992LYO1M059.
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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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Santos, Bruno Lopes dos. "Análise de preditores clínicos e genéticos para o surgimento de discinesias induzidas por L-DOPA na doença de Parkinson." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17140/tde-06042018-094440/.
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A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum do mundo, e seu tratamento atual se baseia principalmente no uso de medicações que facilitam a transmissão dopaminérgica nos núcleos da base. A L-DOPA é a principal medicação usada no tratamento da DP, contudo seu uso crônico está associado ao surgimento de complicações motoras, como as discinesias induzidas por L-DOPA (DIL). As DIL ocorrem em cerca de 50% dos pacientes com DP que usaram LDOPA por cerca de 4 a 6 anos, e podem causar uma série de impactos negativos aos pacientes. Pela incapacidade adicional que esta complicação traz aos pacientes com DP, a definição de fatores que possam predizer o surgimento das DIL é de importância direta para o clínico que prescreve L-DOPA rotineiramente. O objetivo deste estudo foi determinar os principais fatores de risco clínicos e genéticos para o desenvolvimento de DIL em uma casuística de pacientes brasileiros com DP. Um estudo transversal foi realizado em pacientes brasileiros de dois centros (Ribeirão Preto e São Paulo) como parte do projeto \"Latin American Research Consortium on the Genetics of PD\" (LARGE-PD), incluindo apenas pacientes com DP e em uso de L-DOPA. A avaliação foi baseada em um exame neurológico completo e em uma entrevista semi-estruturada feita por um médico neurologista especialista em Distúrbios de Movimentos. A presença de DIL foi considerada se a pontuação fosse >= 1 no item 32 da Parte IV na MDS-UPDRS. Baseados em estudos prévios, nós escolhemos oito polimorfismos tipo single nucleotide polymorphism (SNP) nestes genes: COMT, MAOB, ANKK1, DRD3, DAT1, BDNF, ADORA2A and NOS1. A genotipagem foi realizada através de ensaios TaqMan SNP. Foram realizados modelos de regressão logística e análises de sobrevivência para identificarmos os fatores de risco clínicos e genéticos associados ao surgimento de DIL. Ao todo, foram analisados 199 pacientes (sexo masculino - 59%; idade média 61.8 anos), sendo 96 indivíduos (48.2%) com DIL. Através de um modelo de regressão logística multivariado com 7 variáveis independentes, o fenótipo clínico motor do tipo postural instability with gait disorder (PIGD) (OR 0.17, IC 95% 0.07-0.39; p < 0.001), longos períodos de tratamento com L-DOPA (OR 1.31, IC 95% 1.17-1.47; p < 0.001), altas doses diárias equivalentes de L-DOPA (OR 1.00, IC 95% 1.000-1.002; p = 0.04) e a início precoce dos sintomas da 11 DP (OR 1.04, IC 95% 1.01-1.07; p = 0.009) foram os fatores de risco clínicos mais associados ao surgimento de DIL. Dentre os fatores de risco genéticos, apenas o alelo T do SNP rs1799836 no gene da MAOB esteve associado ao aumento na chance de surgimento de DIL (OR 1.51, IC 95% 1.00-2.28; p = 0.05). Nossos resultados mostraram que a predição de surgimento de DIL em pacientes com DP em uso de L-DOPA pode ser feita através de alguns fatores de risco clínicos (fenótipo clínico motor, duração do tratamento com L-DOPA, dose diária equivalente de L-DOPA e idade de início de sintomas) e genéticos, como o SNPrs1799836 no gene da MAOB. Novos estudos com amostras maiores e desenhos prospectivos longitudinais são necessários para se explorar a associação entre estes preditores e o surgimento de DIL.Parkinson\'s disease (PD) is the second most common neurodegenerative disease in the world, and its treatment is mainly based on drugs involved on dopaminergic neurotransmission in basal ganglia. L-DOPA is the major medication used on the management of PD, but its chronic use is associated with the onset of motor complications, as L-DOPA-induced dyskinesias (LID). LID occur in approximately 50% of patients using L-DOPA over 4 and 6 years, and they cause negative impacts on the quality of life of patients PD. To predict the onset of LID based on clinical and genetic risk may be an useful tool for clinicians which prescribe L-DOPA. The aim of this study was to determinate the main clinical and genetic risk factors for the onset of LID in Brazilian PD patients. A cross-sectional study was conducted with Brazilian PD patients from two centers (Ribeirao Preto and Sao Paulo) as part of the Latin American Research consortium on the Genetics of PD (LARGE-PD), which enrolled only PD patients using L-DOPA. PD patients were submitted to neurological examination and semi-structured interviews performed by movement disorders specialists. Presence of LID was confirmed if UPDRS Part IV had a score >= 1 on item 32. Based on previous studies, we chose eight Single Nucleotide Polymorphisms (SNP) in the following genes: COMT, MAOB, ANKK1, DRD3, DAT1, BDNF, ADORA2A and NOS1. Genotyping was performed using TaqMan SNP genotyping assays. We performed logistic regression and survival analysis to identify clinical and genetic risk factors associated with LID onset We enrolled 199 PD patients (males - 59%; mean age 61.8 years), and 96 patients (48.2%) had LID. At a multivariate model with 7 independent variables, postural instability with gait disorder (PIGD) clinical phenotype (OR 0.17, CI 95% 0.07-0.39; p < 0.001), longer duration of L-DOPA therapy (OR 1.31, Cl 95% 1.17-1.47; p < 0.001), higher L-DOPA equivalent daily doses (OR 1.00, CI 95% 1.000-1.002; p = 0.04), as also as early onset of PD (OR 1.04, CI 95% 1.01-1.07; p = 0.009) were the clinical risk factor more associated with onset of LID. Regarding genetic risk factors, only MAOB SNP rs1799836 was associated with LID, with the T allele increasing the risk of developing LIDs (OR 1.51, CI 95% 1.00-2.28; p = 0.05). Our results showed onset of LID can be predicted based on some clinical (motor clinical phenotype, duration of L-DOPA therapy, L-DOPA equivalent daily dose and age at PD onset) and genetic risk factors, as MAOB SNP rs1799836. Further studies in larger samples, using longitudinal and prospective designs, are needed to explore the association between these predictors and onset of LID.
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Moutinho, Daniela Mesquita. "Human ceruloplasmin and neurotransmitters: complex stabilization and crystallization." Master's thesis, Faculdade de Ciências e Tecnologia, 2013. http://hdl.handle.net/10362/10853.
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Dissertation to obtain a Master Degree in Molecular Genetics and Biomedicine at Faculty of Sciences and Technology,Universidade Nova de LisboaHuman ceruloplasmin (hCp) is the molecular linker between the copper and iron metabolism and its importance in the homeostasis of human body has been implied in some neurological diseases. This plasma cuproenzyme has ferroxidase activity, oxidizing Fe2+ to Fe3+ and incorporating it into apotransferrin. hCp also has aminoxidase activity regulating the levels of amine stress hormones in the bloodstream and brain. Thus, it is thought to have an important role in neurodegenerative diseases such as Alzheimer’s or Parkinson’s. To know more about the role of cerulopalsmin on the oxidation of neurotransmitters and on brain homeostasis it is essential to know which protein residues are implied in the binding and stabilization of these neurotransmitters. The primary source of structural information for protein-ligand complexes is X-ray crystallography. This is the most successful method to determine macromolecular 3D structures but has some limitations as obtaining good diffracting protein crystals. In this study several attempts were made to achieve better hCp diffracting crystals and crystals of hcp in complex with dopamine, L-dopa, epinephrine or serotonin in order to further determine its tridimensional structure. To improve hCp stabilization and solubility, differential scanning fluorimetry and dynamic light scattering were used in a search for a better buffer for crystallization. For hCp crystallization the vapour-diffusion technique was used in combination with several other methods. Commercial crystallization screens, crystal seeding, additives, crosslinking were the several methods used to improve crystal diffraction. Co-crystallization of hCp with neurotransmitters was performed with no success. Soaking of hCp crystals with the neurotransmitters was performed in an attempt to get crystals of the hCpneurotransmitter complexes. All crystals were sent for analysis at European Synchrotron Radiation Facility (ESRF) and structural data will be further processed.
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BELLONNET, CHRISTINE. "Influence de la dietetique sur les fluctuations motrices des parkinsoniens traites par la levodopa." Clermont-Ferrand 1, 1989. http://www.theses.fr/1989CLF13044.
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