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The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease.
Johnson KA, Jones CK, Tantawy MN, Bubser M, Marvanova M, Ansari MS, Baldwin RM, Conn PJ, Niswender CM
(2013) Neuropharmacology 66: 187-95
MeSH Terms: Aminobutyrates, Animals, Benzoates, Catalepsy, Disease Models, Animal, Dopamine, Dopamine D2 Receptor Antagonists, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced, Excitatory Amino Acid Agonists, Forelimb, Glycine, Haloperidol, Injections, Intraventricular, Male, Neostriatum, Parkinsonian Disorders, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D2, Receptors, Metabotropic Glutamate, Reserpine, Time Factors
Show Abstract · Added February 19, 2015
Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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23 MeSH Terms
Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.
Ohlin KE, Francardo V, Lindgren HS, Sillivan SE, O'Sullivan SS, Luksik AS, Vassoler FM, Lees AJ, Konradi C, Cenci MA
(2011) Brain 134: 2339-57
MeSH Terms: Aged, Aged, 80 and over, Analysis of Variance, Animals, Antigens, CD, Antigens, Surface, Antiparkinson Agents, Astrocytes, Behavior, Animal, Benserazide, Blood Vessels, Blood-Brain Barrier, Brain, Bromodeoxyuridine, Cell Count, Cells, Cultured, Disease Models, Animal, Dopamine, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced, Embryo, Mammalian, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Female, Humans, Laminin, Levodopa, Male, Neovascularization, Pathologic, Nerve Tissue Proteins, Parkinsonian Disorders, RNA, Messenger, Rats, Rats, Sprague-Dawley, Time Factors, Up-Regulation, Vascular Endothelial Growth Factor A
Show Abstract · Added May 27, 2014
Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.
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37 MeSH Terms
Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease.
Ahmed MR, Berthet A, Bychkov E, Porras G, Li Q, Bioulac BH, Carl YT, Bloch B, Kook S, Aubert I, Dovero S, Doudnikoff E, Gurevich VV, Gurevich EV, Bezard E
(2010) Sci Transl Med 2: 28ra28
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents, Behavior, Animal, Dose-Response Relationship, Drug, Dyskinesias, Endocytosis, G-Protein-Coupled Receptor Kinases, Gene Knockdown Techniques, Genetic Therapy, Humans, Lentivirus, Levodopa, Macaca, Oxidopamine, Parkinsonian Disorders, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1, Receptors, Dopamine D2, Rotation, Signal Transduction
Show Abstract · Added December 10, 2013
Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor l-dopa is the mainstay of current treatment. After several years, however, the patients develop l-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of l-dopa and even prolonged the antiparkinsonian effect of a lower dose of l-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of l-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.
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22 MeSH Terms
5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease.
Ferguson MC, Nayyar T, Deutch AY, Ansah TA
(2010) Neuropharmacology 59: 31-6
MeSH Terms: Animals, Antiparkinson Agents, Brain, Disability Evaluation, Disease Models, Animal, Dose-Response Relationship, Drug, Dyskinesias, Fluorobenzenes, Indoles, Levodopa, Male, Mice, Mice, Inbred C57BL, Parkinson Disease, Parkinsonian Disorders, Piperidines, Pyridines, Ritanserin, Serotonin 5-HT2 Receptor Antagonists, Serotonin Antagonists, Treatment Outcome
Show Abstract · Added May 27, 2014
Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease.
Published by Elsevier Ltd.
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21 MeSH Terms
Cortical regulation of striatal medium spiny neuron dendritic remodeling in parkinsonism: modulation of glutamate release reverses dopamine depletion-induced dendritic spine loss.
Garcia BG, Neely MD, Deutch AY
(2010) Cereb Cortex 20: 2423-32
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Analysis of Variance, Animals, Cerebral Cortex, Corpus Striatum, Dendrites, Disease Models, Animal, Dopamine, Excitatory Amino Acid Agents, Fluoresceins, Glutamic Acid, Male, Neurons, Organ Culture Techniques, Organic Chemicals, Oxidopamine, Parkinsonian Disorders, Rats, Rats, Sprague-Dawley, Silver Staining
Show Abstract · Added May 27, 2014
Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion-induced spine loss by placing motor cortex lesions 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release completely blocked spine loss in dopamine-denervated cultures. These studies provide the first evidence to show that MSN spine loss associated with parkinsonism can be reversed and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson's disease.
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20 MeSH Terms
Cortical serotonin and norepinephrine denervation in parkinsonism: preferential loss of the beaded serotonin innervation.
Nayyar T, Bubser M, Ferguson MC, Neely MD, Shawn Goodwin J, Montine TJ, Deutch AY, Ansah TA
(2009) Eur J Neurosci 30: 207-16
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Aged, Aged, 80 and over, Animals, Cell Count, Cerebral Cortex, Denervation, Dopamine, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Norepinephrine, Parkinsonian Disorders, Serotonin
Show Abstract · Added May 27, 2014
Parkinson's Disease (PD) is marked by prominent motor symptoms that reflect striatal dopamine insufficiency. However, non-motor symptoms, including depression, are common in PD. It has been suggested that these changes reflect pathological involvement of non-dopaminergic systems. We examined regional changes in serotonin (5-HT) and norepinephrine (NE) systems in mice treated with two different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment paradigms, at survival times of 3 or 16 weeks after the last MPTP injection. MPTP caused a decrease in striatal dopamine concentration, the magnitude of which depended on the treatment regimen and survival interval after MPTP treatment. There was significant involvement of other subcortical areas receiving a dopamine innervation, but no consistent changes in 5-HT or NE levels in subcortical sites. In contrast, we observed an enduring decrease in 5-HT and NE concentrations in both the somatosensory cortex and medial prefrontal cortex (PFC). Immunohistochemical studies also revealed a decrease in the density of PFC NE and 5-HT axons. The decrease in the cortical serotonergic innervation preferentially involved the thick beaded but not smooth fine 5-HT axons. Similar changes in the 5-HT innervation of post-mortem samples of the PFC from idiopathic PD cases were seen. Our findings point to a major loss of the 5-HT and NE innervations of the cortex in MPTP-induced parkinsonism, and suggest that loss of the beaded cortical 5-HT innervation is associated with a predisposition to the development of depression in PD.
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16 MeSH Terms
In-vivo PET imaging of implanted human retinal pigment epithelium cells in a Parkinson's disease rat model.
Wang R, Zhang J, Guo Z, Shen L, Shang A, Chen Y, Yao S, He T, Yin D, Tian J
(2008) Nucl Med Commun 29: 455-61
MeSH Terms: Animals, Cell Differentiation, Epithelial Cells, Female, Humans, Parkinsonian Disorders, Pigment Epithelium of Eye, Positron-Emission Tomography, Rats, Rats, Sprague-Dawley
Show Abstract · Added December 10, 2013
BACKGROUND AND AIM - Researchers find that monitoring the differentiation of implanted cells in vivo is difficult. This study was designed to show that it is possible to track the efficacy of transplanted human retinal pigment epithelial cells (RPE cells) in a rat model of Parkinson's disease by using positron emission tomography (PET).
METHODS - RPE cells or normal saline were injected into striatum of the injured side of the rat model in treated and control groups, respectively. PET imaging of both groups was undertaken before transplantation and at intervals afterwards, using C-raclopride and C-beta-CFT as the markers. Observation of the rats' behaviour and immunofluorescence confocal microscopy were also used to prove the PET results.
RESULTS - PET studies showed increased accumulation of C-raclopride and decreased C-beta-CFT in the injured side of striatum in both groups. C-raclopride decreased along with a concomitant increase of C-beta-CFT after transplantation in the treated group. The changes shown by the PET studies paralleled the behavioural states and confocal microscopy observations in the treated animals.
CONCLUSION - These results suggest that even a clinical PET scanner could, to a certain extent, provide some information on the existence and in-vivo differentiation of RPE cells in a rat model of Parkinson's disease.
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10 MeSH Terms
Striatal plasticity and medium spiny neuron dendritic remodeling in parkinsonism.
Deutch AY, Colbran RJ, Winder DJ
(2007) Parkinsonism Relat Disord 13 Suppl 3: S251-8
MeSH Terms: Animals, Corpus Striatum, Dendrites, Disease Models, Animal, Neuronal Plasticity, Neurons, Parkinsonian Disorders
Show Abstract · Added May 27, 2014
Current approaches to Parkinson's Disease (PD) are largely based on our current understanding of the mechanisms that contribute to the death of nigrostriatal dopamine neurons. However, our understanding of the consequences of the loss of dopamine on the striatal target cells of nigrostriatal neurons is much less advanced. In particular, the compensatory changes that occur in striatal medium spiny neurons (MSNs) that have lost their normal dopamine input remains poorly understood. The compensatory changes may have either positive or negative effects. Among the alterations that occur in striatal cells of the dopamine-denervated striatum are dystrophic changes in the dendrites of MSNs, with a loss of dendritic length and dendritic spine number. Dendritic spines are the targets of convergent nigrostriatal dopamine and corticostriatal glutamate axons, and integrate these convergent signals to determine the nature of striatal output. The loss of these spines in the dopamine-denervated state may protect the MSN from overt excitotoxic death, but at the price of compromising MSN function. The loss of dendritic spines is thought be responsible for the gradual decrease in levodopa efficacy in late-stage PD, suggesting that therapeutic interventions need to be developed that target key downstream signaling complexes in medium spiny neurons.
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7 MeSH Terms
Splicing fidelity, enhancers, and disease.
Solis AS, Shariat N, Patton JG
(2008) Front Biosci 13: 1926-42
MeSH Terms: Alternative Splicing, Animals, Chromosome Mapping, Enhancer Elements, Genetic, Exons, Gene Silencing, Growth Hormone, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Introns, Muscular Dystrophies, Mutation, Parkinsonian Disorders, RNA Splicing, Spliceosomes
Show Abstract · Added May 27, 2014
Eukaryotic pre-mRNA splicing allows for a large, diverse proteome to be coded by a relatively small genome. Alternative splicing events are well regulated, but when mutations disrupt the splice sites or regulatory elements, disease can occur. Similarly, mutations can cause disease through aberrant transcript production. Enhancers, one of the splicing regulatory elements, are frequent targets of disease causing mutations. This review provides an overview of the splicing reaction and mechanisms of alternative splicing and provides examples of enhancer defects that cause disease.
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15 MeSH Terms
Decreased striatal levels of PEP-19 following MPTP lesion in the mouse.
Sköld K, Svensson M, Nilsson A, Zhang X, Nydahl K, Caprioli RM, Svenningsson P, Andrén PE
(2006) J Proteome Res 5: 262-9
MeSH Terms: Animals, Corpus Striatum, In Situ Hybridization, MPTP Poisoning, Male, Mice, Mice, Inbred C57BL, Nerve Degeneration, Nerve Tissue Proteins, Parkinsonian Disorders, Peptides, RNA, Messenger, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added March 5, 2014
PEP-19 is a neuronal calmodulin-binding protein, and as such, a putative modulator of calcium regulated processes. In the present study, we used proteomics technology approaches such as peptidomics and imaging MALDI mass spectrometry, as well as traditional techniques (immunoblotting and in situ hybridization) to identify PEP-19 and, specifically, to measure PEP-19 mRNA and protein levels in an animal model of Parkinson's disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice resulted in a significant decrease in striatal PEP-19 mRNA. Capillary nano-flow liquid chromatography electrospray mass spectrometry analysis of striatal tissue revealed a significant decrease of the PEP-19 protein level. Moreover, imaging MALDI mass spectrometry also showed that PEP-19 protein was predominantly localized to the striatum of the brain tissue cross sections. After MPTP administration, PEP-19 levels were significantly reduced by 30%. We conclude that PEP-19 mRNA and protein expression are decreased in the striatum of a common animal model of Parkinson's disease. Further studies are needed to show the specific involvement of PEP-19 in the neurodegeneration seen in MPTP lesioned animals. Finally, this study has shown that the combination of traditional molecular biology techniques with novel, highly specific and sensitive mass spectrometry methods is advantageous in characterizing molecular events of many diseases, including Parkinson's disease.
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13 MeSH Terms