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1
Darbin, Olivier, Xingxing Jin, Christof Von Wrangel, Kerstin Schwabe, Atsushi Nambu, Dean K. Naritoku, Joachim K. Krauss, and Mesbah Alam. "Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson’s Disease." International Journal of Neural Systems 26, no. 02 (February 21, 2016): 1550038. http://dx.doi.org/10.1142/s0129065715500380.
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The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25[Formula: see text]Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25[Formula: see text]Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.
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Pangestiningsih, Tri Wahyu, Woro Danur Wendo, Yulfia Nelymalik Selan, Filphin Adolfin Amalo, Nemay Anggadewi Ndaong, and Victor Lenda. "Histological Features of Catecholaminergic Neuron in Substantia Nigra Induced by Paraquat Dichloride (1,1-dimethyl-4,4 bipyridinium) in Wistar Rat as A Model of Parkinson Disease." Indonesian Journal of Biotechnology 19, no. 1 (December 31, 2015): 91. http://dx.doi.org/10.22146/ijbiotech.8638.
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Paraquat dichloride has been used by farmers as a herbicide to kill the grass. On the other hand, paraquatdichloride is harmful if enters to the body, causing Parkinson’s disease, since it is disrupting dopamineproduction in the substantia nigra pars compacta or dopamine pathways Nigro striatal pathway. The studywas done to fi nd out the histological changes of catecholaminergic neurons and Nigro striatal pathway causedby paraquat dichloride treatment in Wistar rats as a model of Parkinson’s disease.Twenty-two Wistar rats 3,5 months old were divided into 4 groups, 5 rats each. Group I (control group)were injected with aquabidest, while groups II, III, and IV were injected intraperitoneally with paraquatdichloride in aquabidest, with the dosage 5 , 10 and 15 mg/kg bw respectively. The rats were injected onceper week for 6 weeks. Three days after the last injection, the rats were anesthetized using xylasin (2 mg/kg)and ketamine (20 mg/kg) intramuscularly, and then were intracardiac perfused using physiological saline asprerinse solution, followed by 10% buffered formalin solution as a fi xative. After animals were fi xed, the brainswere removed and embedded in paraffi n block and cut in 12 μm thickness for immunohistochemistry stainingusing tyrosine hydroxylase antibody. The results of staining then were observed under light microscope andanalyzed descriptively.The results showed that the catecholaminergic neurons were distributed in the substantia nigrapars compacta in all treatment groups, however, the cell density were found decreased only in group IV.Catecholaminergic neurons appear in the bipolar and multipolar form, while dopamine ‘Nigro striatal pathway’was found exist in all treatment groups. From our study, histologycally the decreased of catecholaminergicneurons is only found in rats that received paraquat dichloride in dose 15 mg/kg bw for 6 weeks.
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Barbagallo, Gaetano, Maria Sierra-Peña, Federico Nemmi, Anne Pavy-Le Traon, Wassilios G. Meissner, Olivier Rascol, and Patrice Péran. "Multimodal MRI assessment of nigro-striatal pathway in multiple system atrophy and Parkinson disease." Movement Disorders 31, no. 3 (December 17, 2015): 325–34. http://dx.doi.org/10.1002/mds.26471.
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Hongyan, Zhu, Pei Xiao, Wu Lingyan, Liu Bo, Qi Zeming, and Wang Yuyin. "Synchrotron FTIR Microspectroscopy Study of the Striatum in 6-Hydroxydopamine Rat Model of Parkinson's Disease." Spectroscopy: An International Journal 27 (2012): 229–38. http://dx.doi.org/10.1155/2012/176937.
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In the present study, synchrotron-based Fourier transform-infrared (FTIR) microspectroscopy is used to analyze the biochemical composition of the striatal neurons in normal and Parkinson's disease (PD) rat brain tissues. The rat model of Parkinson's disease is established by destroying the nigrostriatal pathway with 6-hydroxydopamine (6-OHDA). The detailed spectral analyses show the significant changes of cellular compositions such as lipids, and proteins in the striatal neurons of 6-OHDA-lesioned PD rats with respect to control neurons. As a result, the intensities of spectral absorption assigned to lipid of the striatal neurons in PD rats are higher than in control animals. Furthermore, the unsaturation levels of phospholipids decrease in PD neurons with respect to control neurons, indicating a high level of lipid peroxidation. The analysis of protein secondary structure shows the significantly higher ratio ofβ-sheet in PD neurons compared to that of control neurons, suggesting that the abnormal protein structure occurs before their morphological appearances in the striatal neurons. These findings suggest that the biochemical changes in neurons could be involved in the pathogenesis of Parkinson's disease.
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Edwards III, Gamez, Armijo, Kramm, Morales, Taylor-Presse, Schulz, Soto, and Moreno-Gonzalez. "Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson’s Disease-Associated Pathology." Cells 8, no. 11 (October 30, 2019): 1359. http://dx.doi.org/10.3390/cells8111359.
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: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.
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Burbach, J. P. H., P. Cazorla, and M. P. Smidt. "Molecular players in the development and maintenance of mesencephalic dopamine systems." Acta Neuropsychiatrica 11, no. 2 (June 1999): 71–73. http://dx.doi.org/10.1017/s0924270800036206.
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Several psychiatric diseases are considered to be neuro-developmental disorders. Amongst these are schizophrenia and autism, in which genetic and environmental components have been indicated. In these disorders intrinsic molecular mechanisms of brain development may be deranged due to genetic predispositions, or modified by external influences. Brain development is a delicate process of well-tuned cellular proliferation and differentiation of multipotent neural progenitor cells driven by spatiotemporal cues. One of the fundamental mechanisms is the interaction between external signals, e.g. growth factors, and internal regulators, e.g. transcription factors. An important transmitter system involved in behavioural and affective functions relevant for psychiatric disorders is the mesencephalic dopamine (DA) system. The mesencephalic DA system is organized in two anatomically and functionally different systems. DA neurons in the ventral tegmental area project to the mesolimbic system and are mostly related to control of behaviour. It has been implicated in drug addiction and affective disorders like dipolar disorder and schizophrenia. The dopamine system of the substantia nigra (nigro-striatal pathway) is implicated in movement control. Degeneration of this system, as in Parkinson's disease, or altered function in tardive dyskinesia have highlighted its importance in human disease. Recent findings in molecular neurobiology have provided the first clues to molecular mechanisms involved in developing and mature DA neurons. These may have clinical implications in novel therapeutic strategies.
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Morari, Michele, and Martina Fantin. "Loss of the preferential control over the striato-nigral direct pathway by striatal NMDA receptors in a rat model of Parkinson's disease." Analyst 140, no. 11 (2015): 3830–39. http://dx.doi.org/10.1039/c4an01918k.
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Anselmi, Laura, Jessica Hampton, Cecilia Bove, and R. Alberto Travagli. "The Nigro-Vagal Pathway is Impaired Prior to Motor Pathways in an Experimental Model of Parkinson's Disease." Gastroenterology 152, no. 5 (April 2017): S925. http://dx.doi.org/10.1016/s0016-5085(17)33156-6.
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Kuten, Jonathan, Adi Linevitz, Hedva Lerman, Nanette Freedman, Meir Kestenbaum, Tamara Shiner, Nir Giladi, and Einat Even-Sapir. "[18F] FDOPA PET may confirm the clinical diagnosis of Parkinson's disease by imaging the nigro-striatal pathway and the sympathetic cardiac innervation: Proof-of-concept study." Journal of Integrative Neuroscience 19, no. 3 (2020): 489. http://dx.doi.org/10.31083/j.jin.2020.03.196.
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Mehta, V., J. Spears, and I. Mendez. "Neural Transplantation in Parkinson's Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 24, no. 04 (November 1997): 292–301. http://dx.doi.org/10.1017/s0317167100032959.
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ABSTRACT:Parkinson's disease is a neurodegenerative disorder that affects about 1% of Canadians between the ages of fifty and seventy. The medical management for these patients consists of drug therapy that is initially effective but has limited long term benefits and does not alter the progressive course of the disease. The recalcitrance of longstanding Parkinson's disease to medical management has prompted the use of alternative surgical therapies. Many neurosurgical procedures have been utilized in order to improve the disabling symptoms these patients harbour. Although most of the current procedures involve making destructive lesions within various basal ganglia nuclei, neural transplantation attempts to reconstitute the normal nigrostriatal pathway and restore striatal dopamine. The initial success of neural transplantation in the rodent and primate parkinsonian models has led to its clinical application in the treatment of parkinsonian patients. Currently, well over one hundred patients throughout the world have been grafted with fetal tissue in an effort to ameliorate their parkinsonian symptoms. Although the results of neural transplantation in clinical trials are promising, a number of issues need to be resolved before this technology can become a standard treatment option. This review focuses on the current status of neural transplantation in Parkinson's disease within the context of other surgical therapies in current use.
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Nanni, Giorgia, and R. Alberto Travagli. "224 A NIGRO-VAGAL PATHWAY CONTROLS COLONIC MOTILITY AND MAY BE IMPAIRED IN A MODEL OF ENVIRONMENTAL PARKINSON'S DISEASE." Gastroenterology 158, no. 6 (May 2020): S—41. http://dx.doi.org/10.1016/s0016-5085(20)30785-x.
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Jahanshahi, M., J. Rowe, T. Saleem, R. G. Brown, P. Limousin-Dowsey, J. C. Rothwell, D. G. T. Thomas, and N. P. Quinn. "Striatal Contribution to Cognition: Working Memory and Executive Function in Parkinson's Disease before and after Unilateral Posteroventral Pallidotomy." Journal of Cognitive Neuroscience 14, no. 2 (February 1, 2002): 298–310. http://dx.doi.org/10.1162/089892902317236911.
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The basal ganglia are intimately connected to the frontal cortex via five fronto-striatal circuits. While the role of the frontal cortex in cognition has been extensively studied, the contribution of the basal ganglia to cognition has remained less clear. In Parkinson's disease, posteroventral pallidotomy (PVP) involves surgical lesioning of the internal section of the globus pallidus (GPi, the final output pathway from the basal ganglia) to relieve the motor symptoms of the disorder. PVP in Parkinson's disease provides a unique opportunity to investigate the impact of disruption of striatal outflow to the frontal cortex on cognition. We assessed executive function and working memory after withdrawal of medication in 13 patients with Parkinson's disease before and 3 months after unilateral PVP compared to 12 age-and IQ-matched normals assessed twice with an interval of 3 months. The tests used were: Wisconsin Card Sorting (WCST), Self-Ordered Random Number Sequences, Missing Digit Test, Paced Visual Serial Addition Test (PVSAT), and Visual Conditional Associative Learning Test (VCALT). After PVP, the patients performed significantly better on the Self-Ordered Random Number Sequences and the WCST, an improvement that was also observed in the normals across the two assessment and is therefore likely to reflect practice effects. Relative to the normals, the patients showed significant differential change following PVP on the Missing Digit Test and PVSAT, on which they performed worse after compared to before surgery, while the controls performed better on the second assessment. For the patients, performance on the VCALT also indicated deterioration after PVP, but the changes approached significance. The side of PVP had no effect on the results. The pattern of change observed 3 months after PVP was maintained at 15-month follow-up. The results suggest that striatal outflow to the frontal cortex may be essential for those aspects of executive function that showed deterioration after PVP. &
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Centonze, Diego, Paolo Gubellini, Barbara Picconi, Paolo Calabresi, Patrizia Giacomini, and Giorgio Bernardi. "Unilateral Dopamine Denervation Blocks Corticostriatal LTP." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 3575–79. http://dx.doi.org/10.1152/jn.1999.82.6.3575.
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The nigrostriatal dopaminergic projection is crucial for the striatal processing of motor information received from the cortex. Lesion of this pathway in rats causes locomotor alterations that resemble some of the symptoms of Parkinson's disease and significantly alters the excitatory transmission in the striatum. We performed in vitro electrophysiological recordings to study the effects of unilateral striatal dopamine (DA) denervation obtained by omolateral nigral injection of 6-hydroxydopamine (6-OHDA) in the formation of corticostriatal long-term potentiation (LTP). Unilateral nigral lesion did not affect the intrinsic membrane properties of striatal spiny neurons. In fact, these cells showed similar pattern of firing discharge and current-voltage relationship in denervated striata and in naive controlateral striata. Moreover, excitatory postsynaptic potentials (EPSPs) evoked by stimulating corticostriatal fibers and recorded from DA-denervated slices showed a pharmacology similar to that observed in slices obtained from controlateral intact striata. Conversely, in magnesium-free medium, high-frequency stimulation (HFS) of corticostriatal fibers produced LTP in slices from nondenervated striata but not in slices from 6-OHDA–denervated rats. After denervation, in fact, no significant changes in the amplitude of extra- and intracellular synaptic potentials were recorded after the conditioning HFS. The absence of corticostriatal LTP in DA-denervated striata might represent the cellular substrate for some of the movement disorders observed in Parkinson's disease.
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Durrenberger, Pascal F., Edna Grünblatt, Francesca S. Fernando, Camelia Maria Monoranu, Jordan Evans, Peter Riederer, Richard Reynolds, and David T. Dexter. "Inflammatory Pathways in Parkinson’s Disease; A BNE Microarray Study." Parkinson's Disease 2012 (2012): 1–16. http://dx.doi.org/10.1155/2012/214714.
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The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene,ALDH1A1(Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation ofP2X7(purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on theNOS3(nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth.
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Singh, Arun, Li Liang, Yoshiki Kaneoke, Xuebing Cao, and Stella M. Papa. "Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates." Journal of Neurophysiology 113, no. 5 (March 1, 2015): 1533–44. http://dx.doi.org/10.1152/jn.00910.2014.
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Nigrostriatal dopamine denervation plays a major role in basal ganglia circuitry disarray and motor abnormalities of Parkinson's disease (PD). Studies in rodent and primate models have revealed that striatal projection neurons, namely, medium spiny neurons (MSNs), increase the firing frequency. However, their activity pattern changes and the effects of dopaminergic stimulation in such conditions are unknown. Using single-cell recordings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates with advanced parkinsonism, we studied MSN activity patterns in the transition to different motor states following levodopa administration. In the “off” state (baseline parkinsonian disability), a burst-firing pattern accompanied by prolonged silences (pauses) was found in 34% of MSNs, and 80% of these exhibited a levodopa response compatible with dopamine D1 receptor activation (direct pathway MSNs). This pattern was highly responsive to levodopa given that bursting/pausing almost disappeared in the “on” state (reversal of parkinsonism after levodopa injection), although this led to higher firing rates. Nonbursty MSNs fired irregularly with marked pausing that increased in the on state in the MSN subset with a levodopa response compatible with dopamine D2 receptor activation (indirect pathway MSNs), although the pause increase was not sustained in some units during the appearance of dyskinesias. Data indicate that the MSN firing pattern in the advanced parkinsonian monkey is altered by bursting and pausing changes and that dopamine differentially and inefficiently regulates these behaviorally correlated patterns in MSN subpopulations. These findings may contribute to understand the impact of striatal dysfunction in the basal ganglia network and its role in motor symptoms of PD.
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Ghalami, Jamileh, Tourandokht Baluchnejad Mojarad, Monireh Mansouri, Safoura Khamse, and Mehrdad Roghani. "Paeonol Protection Against Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease." Basic and Clinical Neuroscience Journal 12, no. 1 (January 1, 2021): 43–56. http://dx.doi.org/10.32598/bcn.12.6.88.7.
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Introduction: Parkinsonchr('39')s disease (PD) presentations comprise frequent movement disorders in the elderly with various symptoms consisting of motor and non-motor complications. Paeonol is a phenolic chemical agent that has shown antioxidant and anti-inflammatory effects in different disorders and promising effects on metabotropic glutamate receptors (mGluR)- and GABAA-mediated neurotransmission. In this research, we tried to show the neuroprotective potential of paeonol in rat PD model induced by intrastriatal 6-hydroxydopamine (6-OHDA). Methods: Rats with intrastriatal 6-OHDA lesioning received with paeonol at a dosage of 100 mg/kg/d for one week. In the end, some biomarkers of oxidative stress, apoptosis, and astrogliosis in nigral and striatal tissues were evaluated in addition to behavioral and Tyrosine Hydroxylase (TH) immunohistochemical analysis. Results: The obtained data showed that paeonol alleviates apomorphine-induced rotations and reduces the delay time to initiate and the total time in the narrow beam test. However, its beneficial behavioral effect vanished after intracerebroventricular administration of mGluR III or GABAA receptor antagonists. Moreover, paeonol significantly restored striatal malondialdehyde, tissue levels of reactive oxygen species, the activity of the protective and vital enzymes consisting of superoxide dismutase and catalase, Glial Fibrillary Acidic Protein (GFAP), DNA fragmentation, phosphor apoptosis signal-regulating kinase 1, and nigral aquaporin 4 with no significant and proper change of nitrite, interleukin-1β, inducible nitric oxide synthase, and angiotensin II. Additionally, paeonol prevented injury and reduced tyrosine hydroxylase-containing neurons in the midbrain nigral tissue. Conclusion: These obtained findings evidently designate neuroprotective property of paeonol in 6-OHDA murine model of PD that is exerted via easing of oxidative stress, apoptosis, astrogliosis, and its advantageous effect is to some extent mediated via mGluR III/GABAA pathway.
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Nanni, Giorgia, Cameron R. Burkholder, Kirsteen N. Browning, and R. Alberto Travagli. "Fr435 CHEMOGENETIC INIHIBITION OF THE NIGRO-VAGAL PATHWAY ATTENUATES PARKINSONISM AND RESTORES THE DELAYED GASTRO-CECAL TRANSIT IN A MODEL OF ENVIRONMENTAL PARKINSON'S DISEASE." Gastroenterology 160, no. 6 (May 2021): S—316. http://dx.doi.org/10.1016/s0016-5085(21)01476-1.
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Aebischer, P., S. R. Winn, P. A. Tresco, C. B. Jaeger, and L. A. Greene. "Transplantation of Polymer Encapsulated Neurotransmitter Secreting Cells: Effect of the Encapsulation Technique." Journal of Biomechanical Engineering 113, no. 2 (May 1, 1991): 178–83. http://dx.doi.org/10.1115/1.2891231.
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Deficits associated with neurological diseases may be improved by the transplantation within the brain lesioned target structure of polymer encapsulated cells releasing the missing neurotransmitter. Surrounding cells with a permselective membrane of appropriate molecular weight cut-off allows inward diffusion of nutrients and outward diffusion of neurotransmitters, but prevents immunoglobulins or immune cells from reaching the transplant. This technique therefore allows transplantation of postmitotic cells across species. It also permits neural grafting of transformed cell lines since the polymer capsule prevents the formation of tumors by physically sequestering the transplanted tissue. In the present study, we compared the ability of dopaminesecreting cells, encapsulated by 2 different methods, to reverse experimental Parkinson’s disease, a neurodegenerative disease characterized by motor disturbances due to a lack of dopamine within the striatum following degeneration of the dopaminergic nigro-striatal pathway. PC12 cells were loaded in polyelectrolyte-based microcapsules or thermoplastic-based macrocapsules and maintained in vitro or transplanted in a rat experimental Parkinson model for 4 weeks. Chemically-induced depolarization increased the in vitro release of dopamine from macrocapsules over time, while no increase in release was observed from microcapsules. Encapsulated PC12 cells were able to reduce lesion-induced rotational asymmetry in rats for at least 4 weeks, regardless of the encapsulation technique used. With both encapsulation methods, PC12 cell viability was greater in vivo than in vitro which suggests that the striatum releases trophic factors for PC12 cells. More brain tissue damage was observed with microcapsules than macrocapsules, possibly the result of the difficulty of manipulating the more fragile microcapsules. Material resembling alginate was observed in the brain parenchyma surrounding the microcapsules, whereas no structural changes were observed with poly (acrylonitrile vinyl chloride) based capsules 4 weeks post-implantation. This fact raises questions about the in vivo stability of polyelectrolyte-based capsules implanted in the nervous system. We conclude that the implantation of polymer-encapsulated cells may provide a means for long-term delivery of neurotransmitters providing adequate encapsulation technology.
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Tong, Youren, and Jie Shen. "Genetic analysis of Parkinson's disease-linked leucine-rich repeat kinase 2." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1042–46. http://dx.doi.org/10.1042/bst20120112.
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Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common genetic cause of PD (Parkinson's disease). To investigate how mutations in LRRK2 cause PD, we generated LRRK2 mutant mice either lacking its expression or expressing the R1441C mutant form. Homozygous R1441C knockin mice exhibit no dopaminergic neurodegeneration or alterations in steady-state levels of striatal dopamine, but they show impaired dopamine neurotransmission, as was evident from reductions in amphetamine-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells as well as impaired dopamine D2 receptor-mediated functions. Whereas LRRK2−/− brains are normal, LRRK2−/− kidneys at 20 months of age develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins, impairment of the autophagy–lysosomal pathway, and increases in apoptotic cell death, inflammatory responses and oxidative damage. Our further analysis of LRRK2−/− kidneys at multiple ages revealed unique age-dependent biphasic alterations of the autophagic activity, which is unchanged at 1 month of age, enhanced at 7 months, but reduced at 20 months. Levels of α-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in LRRK2−/− kidneys at 7 months of age. Interestingly, this biphasic alteration is associated with increased levels of lysosomal proteins and proteases as well as progressive accumulation of autolysosomes and lipofuscin granules. We conclude that pathogenic mutations in LRRK2 impair the nigrostriatal dopaminergic pathway, and LRRK2 plays an essential role in the dynamic regulation of autophagy function in vivo.
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Nash, Joanne E., and Jonathan M. Brotchie. "A Common Signaling Pathway for Striatal NMDA and Adenosine A2aReceptors: Implications for the Treatment of Parkinson's Disease." Journal of Neuroscience 20, no. 20 (October 15, 2000): 7782–89. http://dx.doi.org/10.1523/jneurosci.20-20-07782.2000.
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Ding, Shengyuan, Li Li, and Fu-Ming Zhou. "Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output." Journal of Neurophysiology 113, no. 6 (March 15, 2015): 1697–711. http://dx.doi.org/10.1152/jn.00752.2014.
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In Parkinson's disease (PD), the dopamine (DA) neuron loss in the substantia nigra and the DA axon loss in the dorsal striatum are severe, but DA neurons in the ventral tegmental area and DA axons in middle and ventral striatal subregions are less affected. Severe DA loss leads to DA receptor supersensitivity, but it was not known whether the supersensitivity of the DA D1 receptors (D1Rs) on the striatonigral axon terminal is determined by the severe striatal or nigral DA loss. This question is important because these two possibilities affect the extent of the striatonigral terminals with supersensitive D1Rs and hence the strength of the direct pathway output. Here we have investigated this question in the transcription factor Pitx3 mutant mice that have a PD-like DA loss pattern. We found that the presynaptic D1R function was upregulated globally: the D1R-mediated facilitation was equally enhanced for the striatonigral GABA output originated in the dorsal striatum where the DA loss is severe and the somatic D1Rs are supersensitive, and for the striatonigral GABA output originated in the middle and ventral striatum where the DA loss is moderate and the somatic D1Rs are not supersensitive. These results suggest that severe nigral DA loss is sufficient to induce functional upregulation of the D1Rs on striatonigral axon terminals. Consequently, in PD, the globally enhanced D1Rs on striatonigral axon terminals originated in broad striatal subregions may strongly enhance the striatonigral GABA output upon D1R stimulation, potentially contributing to D1R agonism's profound motor-stimulating effects.
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Samiotaki, Gesthimani, Camilo Acosta, Shutao Wang, and Elisa E. Konofagou. "Enhanced Delivery and Bioactivity of the Neurturin Neurotrophic Factor through Focused Ultrasound—Mediated Blood—Brain Barrier Opening in vivo." Journal of Cerebral Blood Flow & Metabolism 35, no. 4 (January 14, 2015): 611–22. http://dx.doi.org/10.1038/jcbfm.2014.236.
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The blood—brain barrier (BBB) constitutes a major obstacle in brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB noninvasively, locally, and transiently to allow large molecules diffusion. Neurturin (NTN), a member of the glial-derived neurotrophic factor (GDNF) family, has been demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. The brain's ascending nigrostriatal pathway is severely damaged in Parkinson's disease (PD), and therefore the substantia nigra (SN) and striatal caudoputamen (CP) were selected as the target areas. The objective of the study was to investigate whether safe and efficient NTN delivery can be achieved through FUS-induced BBB opening via intravenous administration, and thus trigger the neuroregeneration cascade in the nigrostriatal pathway. After the optimization of FUS parameters and target locations in the murine brain, NTN bioavailability and downstream signaling were detected and characterized through immunostaining. FUS significantly enhanced the delivery of NTN compared with the direct injection technique, whereas triggering of the signaling cascade was detected downstream to the neuronal nuclei. These findings thus indicate the potential of the FUS method to mediate transport of proteins through the blood—brain barrier in a PD animal model.
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Kerr, J. N. D., and J. R. Wickens. "Dopamine D-1/D-5 Receptor Activation Is Required for Long-Term Potentiation in the Rat Neostriatum In Vitro." Journal of Neurophysiology 85, no. 1 (January 1, 2001): 117–24. http://dx.doi.org/10.1152/jn.2001.85.1.117.
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Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg2+-free conditions. This Mg2+-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABAA antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.
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Pittman, Julian T., Celia A. Dodd, and Bradley G. Klein. "Immunohistochemical Changes in the Mouse Striatum Induced by the Pyrethroid Insecticide Permethrin." International Journal of Toxicology 22, no. 5 (September 2003): 359–70. http://dx.doi.org/10.1177/109158180302200504.
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Epidemiological studies have linked insecticide exposure and Parkinson's disease. In addition, some insecticides produce damage or physiological disruption within the dopaminergic nigrostriatal pathway of non-humans. This study employed immunohistochemical analysis in striatum of the C57BL/6 mouse to clarify tissue changes suggested by previous pharmacological studies of the pyrethroid insecticide permethrin. Dopamine transporter, tyrosine hydroxylase, and glial fibrillary acidic protein immunoreactivities were examined in caudate-putamen to distinguish changes in amount of dopamine transporter immunoreactive protein from degeneration or other damage to dopaminergic neuropil. Weight-matched pairs of pesticide-treated and vehicle-control mice were dosed and sacrificed on the same days. Permethrin at 0.8, 1.5 and 3.0 mg/kg were the low doses and at 200 mg/kg the high dose. Brains from matched pairs of mice were processed on the same slides using the avidin-biotin technique. Four fields were morphometrically located in each of the serial sections of caudateputamen, digitally photographed, and immunopositive image pixels were counted and compared between members of matched pairs of permethrin-treated and vehicle-control mice. For low doses, only 3.0 mg/kg produced a significant decrease in dopamine transporter immunostaining. The high dose of permethrin did not produce a significant change in dopamine transporter or tyrosine hydroxylase immunostaining, but resulted in a significant increase in glial fibrillary acidic protein immunostaining. These data suggest that a low dose of permethrin can reduce the amount of dopamine transporter immunoreactive protein in the caudate-putamen. They also suggest that previously reported reductions in dopamine uptake of striatal synaptosomes of high-dose mice may be due to nondegenerative tissue damage within this region as opposed to reductions of dopamine transporter protein or death of nigrostriatal terminals. These data provide further evidence that insecticides can affect the primary neurodegenerative substrate of Parkinson's disease.
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Paolini Paoletti, Federico, Lorenzo Gaetani, and Lucilla Parnetti. "The Challenge of Disease-Modifying Therapies in Parkinson’s Disease: Role of CSF Biomarkers." Biomolecules 10, no. 2 (February 19, 2020): 335. http://dx.doi.org/10.3390/biom10020335.
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The development of disease modifying strategies in Parkinson’s disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be a “single entity”. Conversely, in front of the common feature of nigro-striatal degeneration, PD is pathogenically heterogeneous with a series of several biological and molecular pathways that differently contribute to clinical development and progression. Currently available diagnostic criteria for PD mainly rely on clinical features and imaging biomarkers, thus missing to identify the contribution of pathophysiological pathways, also failing to catch abnormalities occurring in the early stages of disease. Cerebrospinal fluid (CSF) is a promising source of biomarkers, with the high potential for reflecting early changes occurring in PD brain. In this review, we provide an overview on CSF biomarkers in PD, discussing their association with different molecular pathways involved either in pathophysiology or progression in detail. Their potential application in the field of disease modifying treatments is also discussed.
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Riestra, AR, MF Lugo, S. Alcauter, C. Garcia, and FA Barrios. "Decreased fractional anisotropy in nigro-striatal tracts in Parkinson's disease." NeuroImage 47 (July 2009): S93. http://dx.doi.org/10.1016/s1053-8119(09)70747-5.
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Poyot, Thomas, Françoise Condé, Marie-Claude Grégoire, Vincent Frouin, Christine Coulon, Chantal Fuseau, Françoise Hinnen, Frédéric Dollé, Philippe Hantraye, and Michel Bottlaender. "Anatomic and Biochemical Correlates of the Dopamine Transporter Ligand 11C-PE2I in Normal and Parkinsonian Primates: Comparison with 6-[18F]Fluoro-L-Dopa." Journal of Cerebral Blood Flow & Metabolism 21, no. 7 (July 2001): 782–92. http://dx.doi.org/10.1097/00004647-200107000-00003.
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Positron emission tomography (PET) coupled to 6-[18F]Fluoro-L-Dopa (18F-Dopa) remains the gold standard for assessing dysfunctionality concerning the dopaminergic nigrostriatal pathway in Parkinson's disease and related disorders. The use of ligands of the dopamine transporters (DAT) is an attractive alternative target; consequently, the current aim was to validate one of them, 11C-PE2I, using a multiinjection modeling approach allowing accurate quantitation of DAT densities in the striatum. Experiments were performed in three controls, three MPTP-treated (parkinsonian) baboons, and one reserpine-treated baboon. 11C-PE2I B′max values obtained with this approach were compared with 18F-Dopa input rate constant values (Ki), in vitro Bmax binding of 125I-PE2I, and the number of dopaminergic neurons in the substantia nigra estimated postmortem by stereology. In the caudate nucleus and putamen, control values for 11C-PE2I B'max were 673 and 658 pmol/mL, respectively, whereas it was strongly reduced in the MPTP-treated (B′max = 26 and 36 pmol/mL) and reserpine-treated animals (B′max = 338 and 483 pmol/mL). In vivo11C-PE2I B′max values correlated with 18F-Dopa Ki values and in vitro125I-PE2I Bmax values in the striatum and with the number of nigral dopaminergic neurons. Altogether, these data support the use of 11C-PE2I for monitoring striatal dopaminergic disorders and the effect of potential neuroprotective strategies.
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Guiney, Stephanie J., Paul A. Adlard, Peng Lei, Celeste H. Mawal, Ashley I. Bush, David I. Finkelstein, and Scott Ayton. "Fibrillar α-synuclein toxicity depends on functional lysosomes." Journal of Biological Chemistry 295, no. 51 (October 7, 2020): 17497–513. http://dx.doi.org/10.1074/jbc.ra120.013428.
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Neurodegeneration in Parkinson's disease (PD) can be recapitulated in animals by administration of α-synuclein preformed fibrils (PFFs) into the brain. However, the mechanism by which these PFFs induce toxicity is unknown. Iron is implicated in PD pathophysiology, so we investigated whether α-synuclein PFFs induce ferroptosis, an iron-dependent cell death pathway. A range of ferroptosis inhibitors were added to a striatal neuron-derived cell line (STHdhQ7/7 cells), a dopaminergic neuron–derived cell line (SN4741 cells), and WT primary cortical neurons, all of which had been intoxicated with α-synuclein PFFs. Viability was not recovered by these inhibitors except for liproxstatin-1, a best-in-class ferroptosis inhibitor, when used at high doses. High-dose liproxstatin-1 visibly enlarged the area of a cell that contained acidic vesicles and elevated the expression of several proteins associated with the autophagy-lysosomal pathway similarly to the known lysosomal inhibitors, chloroquine and bafilomycin A1. Consistent with high-dose liproxstatin-1 protecting via a lysosomal mechanism, we further de-monstrated that loss of viability induced by α-synuclein PFFs was attenuated by chloroquine and bafilomycin A1 as well as the lysosomal cysteine protease inhibitors, leupeptin, E-64D, and Ca-074-Me, but not other autophagy or lysosomal enzyme inhibitors. We confirmed using immunofluorescence microscopy that heparin prevented uptake of α-synuclein PFFs into cells but that chloroquine did not stop α-synuclein uptake into lysosomes despite impairing lysosomal function and inhibiting α-synuclein toxicity. Together, these data suggested that α-synuclein PFFs are toxic in functional lysosomes in vitro. Therapeutic strategies that prevent α-synuclein fibril uptake into lysosomes may be of benefit in PD.
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Ruppert, Marina C., Andrea Greuel, Masoud Tahmasian, Frank Schwartz, Sophie Stürmer, Franziska Maier, Jochen Hammes, et al. "Network degeneration in Parkinson’s disease: multimodal imaging of nigro-striato-cortical dysfunction." Brain 143, no. 3 (February 14, 2020): 944–59. http://dx.doi.org/10.1093/brain/awaa019.
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Abstract The spreading hypothesis of neurodegeneration assumes an expansion of neural pathologies along existing neural pathways. Multimodal neuroimaging studies have demonstrated distinct topographic patterns of cerebral pathologies in neurodegeneration. For Parkinson’s disease the hypothesis so far rests largely on histopathological evidence of α-synuclein spreading in a characteristic pattern and progressive nigrostriatal dopamine depletion. Functional consequences of nigrostriatal dysfunction on cortical activity remain to be elucidated. Our goal was to investigate multimodal imaging correlates of degenerative processes in Parkinson’s disease by assessing dopamine depletion and its potential effect on striatocortical connectivity networks and cortical metabolism in relation to parkinsonian symptoms. We combined 18F-DOPA-PET, 18F-fluorodeoxyglucose (FDG)-PET and resting state functional MRI to multimodally characterize network alterations in Parkinson’s disease. Forty-two patients with mild-to-moderate stage Parkinson’s disease and 14 age-matched healthy control subjects underwent a multimodal imaging protocol and comprehensive clinical examination. A voxel-wise group comparison of 18F-DOPA uptake identified the exact location and extent of putaminal dopamine depletion in patients. Resulting clusters were defined as seeds for a seed-to-voxel functional connectivity analysis. 18F-FDG metabolism was compared between groups at a whole-brain level and uptake values were extracted from regions with reduced putaminal connectivity. To unravel associations between dopaminergic activity, striatocortical connectivity, glucose metabolism and symptom severity, correlations between normalized uptake values, seed-to-cluster β-values and clinical parameters were tested while controlling for age and dopaminergic medication. Aside from cortical hypometabolism, 18F-FDG-PET data for the first time revealed a hypometabolic midbrain cluster in patients with Parkinson’s disease that comprised caudal parts of the bilateral substantia nigra pars compacta. Putaminal dopamine synthesis capacity was significantly reduced in the bilateral posterior putamen and correlated with ipsilateral nigral 18F-FDG uptake. Resting state functional MRI data indicated significantly reduced functional connectivity between the dopamine depleted putaminal seed and cortical areas primarily belonging to the sensorimotor network in patients with Parkinson’s disease. In the inferior parietal cortex, hypoconnectivity in patients was significantly correlated with lower metabolism (left P = 0.021, right P = 0.018). Of note, unilateral network alterations quantified with different modalities corresponded with contralateral motor impairments. In conclusion, our results support the hypothesis that degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas and impairing motor control in patients with Parkinson’s disease. The present study is the first to reveal trimodal evidence for network-dependent degeneration in Parkinson’s disease by outlining the impact of functional nigrostriatal pathway impairment on striatocortical functional connectivity networks and cortical metabolism.
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David, Fabian J., Miriam R. Rafferty, Julie A. Robichaud, Janey Prodoehl, Wendy M. Kohrt, David E. Vaillancourt, and Daniel M. Corcos. "Progressive Resistance Exercise and Parkinson's Disease: A Review of Potential Mechanisms." Parkinson's Disease 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/124527.
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This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research.
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Bjugstad, Kimberly B., D. Eugene Redmond, Yang D. Teng, J. D. Elsworth, R. H. Roth, B. C. Blanchard, Evan Y. Snyder, and John R. Sladek. "Neural Stem Cells Implanted into MPTP-Treated Monkeys Increase the Size of Endogenous Tyrosine Hydroxylase-Positive Cells Found in the Striatum: A Return to Control Measures." Cell Transplantation 14, no. 4 (April 2005): 183–92. http://dx.doi.org/10.3727/000000005783983098.
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Neural stem cells (NSC) have been shown to migrate towards damaged areas, produce trophic factors, and replace lost cells in ways that might be therapeutic for Parkinson's disease (PD). However, there is very little information on the effects of NSC on endogenous cell populations. In the current study, effects of implanted human NSC (hNSC) on endogenous tyrosine hydroxylase-positive cells (TH+ cells) after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were explored in nonhuman primates. After MPTP damage and in PD, the primate brain is characterized by decreased numbers of dopamine neurons in the substantia nigra (SN) and an increase in neurons expressing TH in the caudate nucleus. To determine how implanted NSC might affect these cell populations, 11 St. Kitts African green monkeys were treated with the selective dopaminergic neurotoxin, MPTP. Human NSC were implanted into the left and right caudate nucleus and the right SN of eight of the MPTP-treated monkeys. At either 4 or 7 months after NSC implants, the brains were removed and the size and number of TH+ cells in the target areas were assessed. The results were compared to data obtained from normal untreated control monkeys and to the three unimplanted MPTP-treated monkeys. The majority of hNSC were found bilaterally along the nigrostriatal pathway and in the substantia nigra, while relatively few were found in the caudate. In the presence of NSC, the number and size of caudate TH+ cells returned to non-MPTP-treated control levels. MPTP-induced and hNSC-induced changes in the putamen were less apparent. We conclude that after MPTP treatment in the primate, hNSC prevent the MPTP-induced upregulation of TH+ cells in the caudate and putamen, indicating that hNSC may be beneficial to maintaining a normal striatal environment.
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Ghanta, Mohan K., P. Elango, and Bhaskar L. V. K. S. "Current Therapeutic Strategies and Perspectives for Neuroprotection in Parkinson’s Disease." Current Pharmaceutical Design 26, no. 37 (October 26, 2020): 4738–46. http://dx.doi.org/10.2174/1381612826666200217114658.
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Parkinson’s disease is a progressive neurodegenerative disorder of dopaminergic striatal neurons in basal ganglia. Treatment of Parkinson’s disease (PD) through dopamine replacement strategies may provide improvement in early stages and this treatment response is related to dopaminergic neuronal mass which decreases in advanced stages. This treatment failure was revealed by many studies and levodopa treatment became ineffective or toxic in chronic stages of PD. Early diagnosis and neuroprotective agents may be a suitable approach for the treatment of PD. The essentials required for early diagnosis are biomarkers. Characterising the striatal neurons, understanding the status of dopaminergic pathways in different PD stages may reveal the effects of the drugs used in the treatment. This review updates on characterisation of striatal neurons, electrophysiology of dopaminergic pathways in PD, biomarkers of PD, approaches for success of neuroprotective agents in clinical trials. The literature was collected from the articles in database of PubMed, MedLine and other available literature resources.
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Mirdamadi, Jasmine L. "Cerebellar role in Parkinson's disease." Journal of Neurophysiology 116, no. 3 (September 1, 2016): 917–19. http://dx.doi.org/10.1152/jn.01132.2015.
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Parkinson's disease (PD) is a common neurodegenerative disorder associated with motor and cognitive impairments. The mechanisms underlying the pathophysiology and treatments have traditionally focused on basal ganglia-thalamo-cortical pathways due to striatal dopamine loss, but more recent evidence has highlighted the role of the cerebellum. In this Neuro Forum article, I review evidence from neuroimaging and noninvasive brain stimulation that demonstrates altered cerebellar activity in PD may be both a pathophysiological and compensatory mechanism depending on dopaminergic medication and symptoms.
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Vargas, Antonio Pedro, and Francisco Eduardo Costa Cardoso. "Impulse control and related disorders in Parkinson’s disease." Arquivos de Neuro-Psiquiatria 76, no. 6 (June 2018): 399–410. http://dx.doi.org/10.1590/0004-282x20180052.
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ABSTRACT Neuropsychiatric disorders are common among patients with Parkinson’s disease and may appear in any stage of the disease. However, these disorders often go undiagnosed and receive insufficient treatment. Observations in recent years have revealed that dopamine replacement therapy may lead to the development or worsening of conditions, such as gambling disorder, compulsive sexual behavior, compulsive buying and binge eating, in addition to punding and dopamine dysregulation syndrome. The pathophysiology of these disorders seems to be related to abnormal dopaminergic stimulation of the basal regions of the basal ganglia, especially via nigro-mesolimbic pathways. The aim of the present study was to perform a literature review on impulsivity, impulse control disorders and related conditions among patients with Parkinson’s disease, with emphasis on their epidemiology, clinical characteristics and treatment.
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Jhamandas, K. H., R. J. Boegman, and R. J. Beninger. "The 1993 Upjohn Award Lecture. Quinolinic acid induced brain neurotransmitter deficits: modulation by endogenous excitotoxin antagonists." Canadian Journal of Physiology and Pharmacology 72, no. 12 (December 1, 1994): 1473–82. http://dx.doi.org/10.1139/y94-213.
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Excitotoxins constitute a group of agents that are capable of activating excitatory amino acid receptors and producing axon-sparing neuronal lesions. Focal injections of the exogenous excitotoxins kainic acid and ibotenic acid result in depletion of neurotransmitter markers in neuronal cell bodies located in areas of injection or in terminal zones of their projections. The discovery of endogenous agents that behave as excitotoxins has generated interest in the idea that excitotoxicity may contribute to the neuronal degeneration associated with a number of neurological diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) which involve selective neurotransmitter deficits. Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite of tryptophan, which has been detected in the central nervous system (CNS), behaves as an excitotoxin. In the mammalian brain QUIN has been localized to glial and immune cells, and its content increases with age. The neuro-excitatory and neurotoxic actions of QUIN are mediated via the Mg2+-sensitive N-methyl-D-aspartate (NMDA) receptor. The toxicity of QUIN, like that of kainate, but not ibotenate, is dependent on the presence of an intact glutamate–aspartate afferent input to the target area. Focal injections of QUIN into the nucleus basalis magnocellularis (nbM), a major source of cholinergic innervation to diencephalic areas, produce sustained loss of cholinergic neuron markers in the neocortex and amygdala. The neurotoxic action of QUIN on nbM results in an impairment of performance on memory-related tasks. Cortical and amygdaloid projecting cholinergic neurons show differential sensitivity to QUIN and other excitotoxic agents. This factor may partly explain the reported discrepancy between mnemonic deficits and the loss of cholinergic markers in the cerebral cortex induced by intra-nbM injections of certain excitotoxins. Cortical muscarinic receptor function is not significantly influenced by QUIN injections into the nbM producing loss of cortical cholinergic neurons. In the striatum, focal QUIN injections have been found to largely replicate the neurotransmitter deficits prevailing in Huntington's disease, an inherited movement disorder. Intrastriatal QUIN produces a profound loss of the NADPH diaphorase staining neurons in the area of injection but relatively spares these in the adjacent transition zone. QUIN is also highly damaging to the striatopallidal enkephalinergic neurons. However, at doses that are neurotoxic to striatal neurons, QUIN and several other excitotoxins produce significant elevations in enkephalin levels both in the striatum and globus pallidus. This elevation reflects the presence of a plasticity in the striatal enkephalinergic neuron population. The metabolic pathway yielding QUIN produces a number of intermediates that act as excitotoxin antagonists. Kynurenic acid, the most potent of these endogenous agents, blocks the action of QUIN and other excitotoxins that act on NMDA and non-NMDA receptors. Picolinic acid, a pyridine monocarboxylic acid, also attenuates QUIN toxicity. However, it only influences excitotoxins that require an intact glutamatergic afferent input to the target area for the expression of their neurotoxic action. Although picolinic acid modulates presynaptic glutamate release in vitro, this action does not entirely explain its restricted anti-excitotoxic action. The presence of several endogenous excitotoxin antagonists in the CNS has important implications for neuron survival. A balance between endogenous excitotoxins and their built-in antagonists may influence the viability of neuronal groups in the CNS. It also suggests a novel strategy for influencing excitotoxicity through elevations in levels of endogenous antagonists. Nicotinylalanine, an enzyme inhibitor, elevates brain kynurenate levels and exhibits potential for anticonvulsant and anti-excitotoxic action. The study of QUIN and related agents holds promise of understanding factors that underlie neuronal damage and developing novel agents to reduce or prevent this damage in areas of the CNS affected in neurodegenerative disease.Key words: quinolinic acid, brain, neurotransmitters, deficits, excitotoxin, antagonists.
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Galet, Benjamin, Manuela Ingallinesi, Jonathan Pegon, Anh Do Thi, Philippe Ravassard, Nicole Faucon Biguet, and Rolando Meloni. "G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease." Journal of Psychiatry & Neuroscience 46, no. 1 (January 1, 2020): E44—E55. http://dx.doi.org/10.1503/jpn.190171.
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Background: In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target. Methods: We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies. Results: Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an “overload” hypothesis for the etiology of the psychiatric symptoms of Parkinson disease. Limitations: Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types. Conclusion: GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.
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El Nebrisi, Eslam, Hayate Javed, Shreesh K. Ojha, Murat Oz, and Safa Shehab. "Neuroprotective Effect of Curcumin on the Nigrostriatal Pathway in a 6-Hydroxydopmine-Induced Rat Model of Parkinson’s Disease is Mediated by α7-Nicotinic Receptors." International Journal of Molecular Sciences 21, no. 19 (October 3, 2020): 7329. http://dx.doi.org/10.3390/ijms21197329.
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Parkinson’s disease (PD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic nigrostriatal neurons. Most of the existing pharmacological approaches in PD consider replenishing striatal dopamine. It has been reported that activation of the cholinergic system has neuroprotective effects on dopaminergic neurons, and human α7-nicotinic acetylcholine receptor (α7-nAChR) stimulation may offer a potential therapeutic approach in PD. Our recent in-vitro studies demonstrated that curcumin causes significant potentiation of the function of α7-nAChRs expressed in Xenopus oocytes. In this study, we conducted in vivo experiments to assess the role of the α7-nAChR on the protective effects of curcumin in an animal model of PD. Intra-striatal injection of 6-hydroxydopmine (6-OHDA) was used to induce Parkinsonism in rats. Our results demonstrated that intragastric curcumin treatment (200 mg/kg) significantly improved the abnormal motor behavior and offered neuroprotection against the reduction of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and caudoputamen. The intraperitoneal administration of the α7-nAChR-selective antagonist methyllycaconitine (1 µg/kg) reversed the neuroprotective effects of curcumin in terms of both animal behavior and TH immunoreactivity. In conclusion, this study demonstrates that curcumin has a neuroprotective effect in a 6-hydroxydopmine (6-OHDA) rat model of PD via an α7-nAChR-mediated mechanism.
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Doudet, Doris J., Richard Jed Wyatt, Eleanor Cannon-Spoor, Richard Suddath, Catherine A. McLellan, and Robert M. Cohen. "6-[F18]Fluoro-L-DOPA and Cerebral Blood Flow in Unilaterally MPTP-Treated Monkeys." Journal of Neural Transplantation and Plasticity 4, no. 1 (1993): 27–38. http://dx.doi.org/10.1155/np.1993.27.
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Intravenous administration ofO15-labeled water and 6-[F18]-L-fluorodopa were used to assess abnormal striatal activity in monkeys after long-term recovery of unilateral lesions of the dopaminergic nigro-striatal system induced by the neurotoxin MPTP. PET data were examined in relation to behavioral and biological parameters. Cerebral blood flow and 6-[F18]-L-DOPA uptake were found to be significantly reduced in the lesioned striatum, compared to the unaffected side and to normal controls. There was no correlation between cerebral blood flow and any of the behavioral parameters. The uptake rate constant ofF18-DOPA from blood to striatum and the ratios of striatum to occipital areas were highly correlated to the concentrations of homovanillic acid in the cerebrospinal fluid of the same animals but not to the rotational behavior. This MPTP-inducedmodei of striatal dopamine deficiency in primates presents similarities with idiopathic Parkinson's disease and may be used to evaluate the effects of dopaminergic lesions and transplants on brain function.
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Bove, Cecilia, and R. Alberto Travagli. "Neurophysiology of the brain stem in Parkinson’s disease." Journal of Neurophysiology 121, no. 5 (May 1, 2019): 1856–64. http://dx.doi.org/10.1152/jn.00056.2019.
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Parkinson’s disease (PD) is predominantly idiopathic in origin, and a large body of evidence indicates that gastrointestinal (GI) dysfunctions are a significant comorbid clinical feature; these dysfunctions include dysphagia, nausea, delayed gastric emptying, and severe constipation, all of which occur commonly before the onset of the well-known motor symptoms of PD. Based on a distinct distribution pattern of Lewy bodies (LB) in the enteric nervous system (ENS) and in the preganglionic neurons of the dorsal motor nucleus of the vagus (DMV), and together with the early onset of GI symptoms, it was suggested that idiopathic PD begins in the ENS and spreads to the central nervous system (CNS), reaching the DMV and the substantia nigra pars compacta (SNpc). These two areas are connected by a recently discovered monosynaptic nigro-vagal pathway, which is dysfunctional in rodent models of PD. An alternative hypothesis downplays the role of LB transport through the vagus nerve and proposes that PD pathology is governed by regional or cell-restricted factors as the leading cause of nigral neuronal degeneration. The purpose of this brief review is to summarize the neuronal electrophysiological findings in the SNpc and DMV in PD.
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Droby, Amgad, Inbal Maidan, Yael Jacob, Nir Giladi, Jeffrey M. Hausdorff, and Anat Mirelman. "Distinct Effects of Motor Training on Resting-State Functional Networks of the Brain in Parkinson’s Disease." Neurorehabilitation and Neural Repair 34, no. 9 (July 18, 2020): 795–803. http://dx.doi.org/10.1177/1545968320940985.
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Background. Nigrostriatal dopaminergic loss is a hallmark of Parkinson’s disease (PD) pathophysiology, leading to motor Parkinsonism. Different intervention protocols have shown that motor and cognitive functions improvement in PD occur via the modulation of distinct motor and cognitive pathways. Objective. To investigate the effects of two motor training programs on the brains’ functional networks in PD patients. Methods. Thirty-seven PD patients were prospectively studied. All enrolled patients underwent either treadmill training (TT) (n = 19) or treadmill with virtual reality (TT + VR) (n = 18) for 6 weeks. Magnetic resonance imaging (MRI) scans (3 T) acquiring 3-dimensional T1-weighted and resting-state functional MRI (rs-fMRI) data sets were performed at baseline and after 6 weeks. Independent component analysis (ICA) was conducted, and functional connectivity (FC) changes within large-scale functional brain networks were examined. Results. In both groups, significant post-training FC decrease in striatal, limbic, and parietal regions within the basal ganglia network, executive control network, and frontal-striatal network, and significant FC increase in the caudate, and cingulate within the sensorimotor network (SMN) were observed. Moreover, a significant time × group interaction was detected where TT + VR training had greater effects on FC levels in the supplementary motor area (SMA) and right precentral gyrus within the SMN, and in the right middle frontal gyrus (MFG) within the cerebellar network. These FC alterations were associated with improved usual and dual-task walking performance. Conclusions. These results suggest that TT with-and-without the addition of a VR component affects distinct neural pathways, highlighting the potential for beneficial neural plasticity in PD. Such distinctive task-specific pathways may foster the facilitation of interventions tailored to the individual needs of PD patients. Registered at Clinicaltrials.gov number: NCT01732653.
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Yusuf, Issa Olakunle, Pei-Hsun Cheng, Hsiu-Mei Chen, Yu-Fan Chang, Chih-Yi Chang, Han-In Yang, Chia-Wei Lin, et al. "Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington’s Disease." Cellular Physiology and Biochemistry 48, no. 2 (2018): 605–17. http://dx.doi.org/10.1159/000491889.
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Background/Aims: Huntington’s disease (HD) is a heritable neurodegenerative disorder, and there is no cure for HD to date. A type of fibroblast growth factor (FGF), FGF9, has been reported to play prosurvival roles in other neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. However, the effects of FGF9 on HD is still unknown. With many similarities in the cellular and pathological mechanisms that eventually cause cell death in neurodegenerative diseases, we hypothesize that FGF9 might provide neuroprotective functions in HD. Methods: In this study, STHdhQ7/Q7 (WT) and STHdhQ111/Q111 (HD) striatal knock-in cell lines were used to evaluate the neuroprotective effects of FGF9. Cell proliferation, cell death and neuroprotective markers were determined via the MTT assay, propidium iodide staining and Western blotting, respectively. The signaling pathways regulated by FGF9 were demonstrated using Western blotting. Additionally, HD transgenic mouse models were used to further confirm the neuroprotective effects of FGF9 via ELISA, Western blotting and immunostaining. Results: Results show that FGF9 not only enhances cell proliferation, but also alleviates cell death as cells under starvation stress. In addition, FGF9 significantly upregulates glial cell line-derived neurotrophic factor (GDNF) and an anti-apoptotic marker, Bcl-xL, and decreases the expression level of an apoptotic marker, cleaved caspase 3. Furthermore, FGF9 functions through ERK, AKT and JNK pathways. Especially, ERK pathway plays a critical role to influence the effects of FGF9 toward cell survival and GDNF production. Conclusions: These results not only show the neuroprotective effects of FGF9, but also clarify the critical mechanisms in HD cells, further providing an insight for the therapeutic potential of FGF9 in HD.
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Lieberman, Philip. "Why we can talk, debate, and change our minds: Neural circuits, basal ganglia operations, and transcriptional factors." Behavioral and Brain Sciences 37, no. 6 (December 2014): 561–62. http://dx.doi.org/10.1017/s0140525x13004093.
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AbstractAckermann et al. disregard attested knowledge concerning aphasia, Parkinson disease, cortical-to-striatal circuits, basal ganglia, laryngeal phonation, and other matters. Their dual-pathway model cannot account for “what is special about the human brain.” Their human cortical-to-laryngeal neural circuit does not exist. Basal ganglia operations, enhanced by mutations on FOXP2, confer human motor-control, linguistic, and cognitive capabilities.
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Filipović, Marko, Maya Ketzef, Ramon Reig, Ad Aertsen, Gilad Silberberg, and Arvind Kumar. "Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons." Journal of Neurophysiology 122, no. 6 (December 1, 2019): 2294–303. http://dx.doi.org/10.1152/jn.00481.2019.
Full textAbstract:
Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the striatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson’s disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.
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Chen, Allen PF, Lu Chen, Thomas A. Kim, and Qiaojie Xiong. "Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease." Biomedicines 9, no. 6 (June 7, 2021): 647. http://dx.doi.org/10.3390/biomedicines9060647.
Full textAbstract:
Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson’s, Schizophrenia, addiction, and Alzheimer’s disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA’s behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia’s dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA’s reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson’s disease, addiction, and Alzheimer’s Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA’s necessity and contribution to the functional plasticity of different striatal regions.
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Cenci, M. Angela. "Glutamatergic pathways as a target for the treatment of dyskinesias in Parkinson's disease." Biochemical Society Transactions 42, no. 2 (March 20, 2014): 600–604. http://dx.doi.org/10.1042/bst20140006.
Full textAbstract:
PD (Parkinson's disease) is characterized by some typical motor features that are caused by striatal dopamine depletion and respond well to dopamine-replacement therapy with L-dopa. Unfortunately, the majority of PD patients treated with L-dopa develop abnormal involuntary movements (dyskinesias) within a few years. The mechanisms underlying the development of LIDs (L-dopa-induced dyskinesias) involve, on one hand, a presynaptic dysregulation of dopamine release and clearance and, on the other hand, an abnormal postsynaptic response to dopamine in the brain. There is a large amount of evidence that these dopamine-dependent mechanisms are modulated by glutamatergic pathways and glutamate receptors. The present article summarizes the pathophysiological role of glutamatergic pathways in LID and reviews pre-clinical and clinical results obtained using pharmacological modulators of different classes and subtypes of glutamate receptors to treat parkinsonian dyskinesias.
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Chen, Shih-Yun, Kuan-Ming Lu, Hsin-An Ko, Ting-Hao Huang, Janice Hsin-Jou Hao, Yu-Ting Yan, Sunny Li-Yun Chang, Sylvia M. Evans, and Fu-Chin Liu. "Parcellation of the striatal complex into dorsal and ventral districts." Proceedings of the National Academy of Sciences 117, no. 13 (March 13, 2020): 7418–29. http://dx.doi.org/10.1073/pnas.1921007117.
Full textAbstract:
The striatal complex of basal ganglia comprises two functionally distinct districts. The dorsal district controls motor and cognitive functions. The ventral district regulates the limbic function of motivation, reward, and emotion. The dorsoventral parcellation of the striatum also is of clinical importance as differential striatal pathophysiologies occur in Huntington’s disease, Parkinson’s disease, and drug addiction disorders. Despite these striking neurobiologic contrasts, it is largely unknown how the dorsal and ventral divisions of the striatum are set up. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and the ventral striata including the D1-direct and D2-indirect pathways. We show that Nolz-1, through the I12b enhancer, represses Dlx1/2, allowing normal migration of striatal neurons to dorsal and ventral locations. We demonstrate that deletion, up-regulation, and down-regulation of Nolz-1 and Dlx1/2 can produce a striatal phenotype characterized by a withered dorsal striatum and an enlarged ventral striatum and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. Our study indicates that the two-tier system of striatal complex is built by coupling of cell-type identity and migration and suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into developing striata.
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Cuenca-Bermejo, Lorena, Elisa Pizzichini, Valeria Gonçalves, María Guillén-Díaz, Elena Aguilar-Moñino, Consuelo Sánchez-Rodrigo, Ana-María González-Cuello, Emiliano Fernández-Villalba, and María Herrero. "A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity." International Journal of Molecular Sciences 22, no. 9 (April 21, 2021): 4341. http://dx.doi.org/10.3390/ijms22094341.
Full textAbstract:
The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.
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Yang, Ying-Lin, Xiao Cheng, Wei-Han Li, Man Liu, Yue-Hua Wang, and Guan-Hua Du. "Kaempferol Attenuates LPS-Induced Striatum Injury in Mice Involving Anti-Neuroinflammation, Maintaining BBB Integrity, and Down-Regulating the HMGB1/TLR4 Pathway." International Journal of Molecular Sciences 20, no. 3 (January 24, 2019): 491. http://dx.doi.org/10.3390/ijms20030491.
Full textAbstract:
Neuroinflammation has been demonstrated to be linked with Parkinson’s disease (PD), Alzheimer’s disease, and cerebral ischemia. Our previous investigation had identified that kaempferol (KAE) exerted protective effects on cortex neuron injured by LPS. In this study, the effects and possible mechanism of KAE on striatal dopaminergic neurons induced by LPS in mice were further investigated. The results showed that KAE improved striatal neuron injury, and increased the levels of tyrosine hydroxylase (TH) and postsynaptic density protein 95 (PSD95) in the striatum of mice. In addition, KAE inhibited the production of pro-inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), reduced the level of monocyte chemotactic protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the striatum tissues. Furthermore, KAE protected blood-brain barrier (BBB) integrity and suppressed the activation of the HMGB1/TLR4 inflammatory pathway induced by LPS in striatum tissues of mice. In conclusion, these results suggest that KAE may have neuroprotective effects against striatum injury that is induced by LPS and the possible mechanisms are involved in anti-neuroinflammation, maintaining BBB integrity, and down-regulating the HMGB1/TLR4 pathway.
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Huang, Dongping, Jing Xu, Jinghui Wang, Jiabin Tong, Xiaochen Bai, Heng Li, Zishan Wang, et al. "Dynamic Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson’s Disease." Parkinson's Disease 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/9349487.
Full textAbstract:
The characteristic brain pathology and motor and nonmotor symptoms of Parkinson’s disease (PD) are well established. However, the details regarding the causes of the disease and its course are much less clear. Animal models have significantly enriched our current understanding of the progression of this disease. Among various neurotoxin-based models of PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model is the most commonly studied model. Here, we provide an overview of the dynamic changes in the nigrostriatal pathway in the MPTP mouse model of PD. Pathophysiological events, such as reductions in the striatal dopamine (DA) concentrations and levels of the tyrosine hydroxylase (TH) protein, depletion of TH-positive nerve fibers, a decrease in the number of TH-positive neurons in the substantia nigra pars compacta (SNpc), and glial activation, are addressed. This article will assist with the development of interventions or therapeutic strategies for PD.
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Bove, Cecilia, Laura Anselmi, and R. Alberto Travagli. "Altered gastric tone and motility response to brain-stem dopamine in a rat model of parkinsonism." American Journal of Physiology-Gastrointestinal and Liver Physiology 317, no. 1 (July 1, 2019): G1—G7. http://dx.doi.org/10.1152/ajpgi.00076.2019.
Full textAbstract:
The majority of patients with Parkinson’s disease (PD) experience gastrointestinal dysfunction. Recently, we described a nigro-vagal pathway that uses dopaminergic (DA) inputs to the dorsal motor nucleus of the vagus (DMV) and A2 area neurons to modulate gastric motility and tone. This pathway is disrupted in a rodent model of PD. The aim of the present study was to test the hypothesis that brain-stem DA modulation of gastric tone and motility is altered in a rodent model of PD. Male Sprague-Dawley rats received three weekly intraperitoneal injections of paraquat (10 mg/kg) or saline (control). In naive conditions, microinjection of DA into the DMV induced a gastroinhibitory response in 100% of animals. In 19 of 28 PQ-treated animals, however, microinjection of DA into the DVC induced a biphasic response, with an initial increase in gastric tone and motility followed by a profound gastroinhibition. The excitatory response to DA microinjection was attenuated by a combination of DA type 1 (DA1)- and DA2-like receptor antagonists. Conversely, the inhibitory response was reduced by the DA2-like receptor antagonist only. Pretreatment with the α2-adrenoceptor antagonist yohimbine did not modulate the response to DA, thus excluding involvement of the A2 area. At the end of the experiments, induction of the Parkinson phenotype was confirmed by the presence of α-synuclein immunoreactivity in the DMV and substantia nigra pars compacta. These data suggest a maladaptive neural plasticity in brain-stem vagal circuits regulating gastric motility in PQ-treated rats that may be responsible for the gastric dysfunction observed in PD models. NEW & NOTEWORTHY After paraquat treatment and induction of Parkinson’s disease, brain-stem dopamine (DA) application induces a biphasic gastric response in the majority of rats, with an initial increase in tone and motility followed by gastroinhibition. The initial increase in gastric tone and motility is mediated via a combined activation of DA type 1 (DA1)- and DA2-like receptors. The inhibitory effects of DA are mediated by DA2-like receptors and are not affected by blockade of adrenergic inputs mediated by α2-adrenoceptors.