UMLS:C0030567 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies in animal models of Parkinson's disease (PD) suggest the potential utility of adenosine A(2A) antagonists in the treatment of this disease. In the present study, unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats received chronic intermittent treatment with the adenosine A(2A) antagonist SCH58261 (5 mg/kg) plus l-DOPA (3 mg/kg) or l-DOPA (6 mg/kg) alone, at doses producing the same intensity of contralateral turning on first administration. Three days after discontinuation of treatments, GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) mRNA was evaluated at cellular level in the globus pallidus (GP) and substantia nigra pars reticulata (SNr) by in situ hybridization. 6-OHDA lesion significantly increased GAD67 mRNA levels in both the GP and SNr ipsilateral to the lesion. Chronic l-DOPA (6 mg/kg), in contrast to SCH58261 plus l-DOPA (3 mg/kg), produced a sensitized contralateral turning indicative of dyskinetic potential and further increased GAD67 mRNA in the GP. In the SNr, a significant decrease in GAD67 mRNA was observed after either treatments. However, while l-DOPA (6 mg/kg) decreased SNr GAD67 mRNA below the intact side, SCH58261 plus l-DOPA (3 mg/kg) brought GAD67 mRNA to the same level of the intact SNr. l-DOPA (3 mg/kg) or SCH58261 (5 mg/kg) alone failed to modify GAD67 mRNA. Results suggest that an increase in GAD67 mRNA in GP and a decrease in SNr might underlie dyskinetic movements induced by chronic l-DOPA. In contrast, the lack of GAD67 mRNA changes in the GP and a less marked inhibition of SNr might correlate with the absence of dyskinetic potential observed after SCH58261 plus l-DOPA.
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PMID:Blockade of A2A receptors plus l-DOPA after nigrostriatal lesion results in GAD67 mRNA changes different from l-DOPA alone in the rat globus pallidus and substantia nigra reticulata. 1476 48

Although dopamine is the main neurotransmitter in the mesostriatal system, recent studies indicate the existence of two nigrostriatal GABAergic projections: one arising from neurons immunoreactive for GABA, glutamic acid decarboxylase (GAD67), and parvalbumin (PV) lying in the substantia nigra pars reticulata (nigrostriatal GABA cells) and the other arising from a subpopulation of dopaminergic neurons lying in the substantia nigra pars compacta and ventral tegmental area, which under normal conditions, contains mRNA for GAD65 (one of the two isoforms of glutamic acid decarboxylase), but which is not immunoreactive for GABA and GAD65 (nigrostriatal dopaminergic [DA]/GABA cells). With the aim of improving our knowledge about the interaction between the nigrostriatal system of both brain hemispheres, we have studied the response of these three components of the mesostriatal system (GABA, DA/GABA, and DA) to the lesion of the contralateral mesostriatal DA pathway, by using morphological and neurophysiological techniques. Our findings show that, in the side contralateral to the lesion, (1) the number of nigrostriatal GABA cells increases from 6% to 17% with respect to the total number of nigrostriatal cells, (2) the soma of DA/GABA cells becomes immunoreactive for GABA and GAD65, and (3) there is an increase in the firing rate and burst activity of DA-neurons, except in those projecting to the striatum, which may be under the action of the GABA hyperactivity. Taken together, our results suggest that the GABAergic components of the mesostriatal projection play a regulatory role on the DA component, activated or upregulated after contralateral DA lesion and are probably addressed to restoring the functional symmetry in basal ganglia and to slowing down the contralateral progression of DA-cell degeneration in Parkinson's disease.
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PMID:Response of the GABAergic and dopaminergic mesostriatal projections to the lesion of the contralateral dopaminergic mesostriatal pathway in the rat. 1537 92

Therapy for Parkinson's disease (PD), a common neurological disorder characterized by pathological degeneration of the nigrostriatal dopaminergic system, remains unsatisfactory. Gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. Among the numerous candidate genes that have been tested as therapeutic agents, those encoding tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I and aromatic L-amino acid decarboxylase all boost dopamine production, while glial cell line-derived neurotrophic factor promotes the survival of dopaminergic neurons and is generally believed to possess the greatest potential for successful restoration of the dopaminergic system. The genes encoding vesicular monoamine transporter-2 and glutamic acid decarboxylase have also produced therapeutic effects in animal models of PD. Both viral and non-viral vectors, each with its particular advantages and disadvantages, have been used to deliver these genes into the brain. Whether or not regulatable expression systems are essential to successful gene therapy for PD remains a critical issue in the clinical application of this emerging treatment. Here we review the current status of gene therapy for PD, including the application of control systems for transgene expression in the brain.
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PMID:Gene therapy for Parkinson's disease: progress and challenges. 1563 12

The subthalamic nucleus (STN) is considered a homogeneous structure composed essentially of projection neurons that exert a profound glutamate-mediated excitatory influence upon the main output structures of the basal ganglia. It is currently the most efficient target for deep brain stimulations designed to alleviate symptoms of Parkinson's disease. STN neurons were analyzed by applying stereological methods and single/double-immunostaining procedures to postmortem material obtained from normal individuals. Besides a multitude of closely packed projection neurons ( approximately 24.7 mum in diameter), the human STN (mean volume, 174.5 +/- 20.4 mm3; total neuronal density, 239.5 +/- 31.9 x 10(3)) contained smaller neurons (approximately 12.2 microm), which displayed glutamic acid decarboxylase (GAD)(65/67) immunoreactivity and shared the morphological features of interneurons described in Golgi studies of primate STN. These putative gamma-aminobutyric acid (GABA)ergic interneurons accounted for 7.5% of the total neuronal population of the STN. Although present throughout the nucleus, they were significantly more numerous in its posterior-ventral-medial sector, which belongs to the limbic/associative functional territory. Many projection neurons located dorsolaterally in the STN showed parvalbumin immunoreactivity and others lying ventromedially displayed calretinin immunostaining, but none of the GAD-positive interneurons expressed these calcium-binding proteins. Although less abundant than projection neurons, GABAergic interneurons might play a important role in the intrinsic organization of the STN. The morphological and chemical heterogeneity of the human STN reported here might have important implications in the functional organization of the basal ganglia.
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PMID:GABAergic interneurons in human subthalamic nucleus. 1564 34

Parkinson's disease (PD) is a good target for gene therapy because the lesion is localized to the substantia nigra (SN). There are several approaches in gene therapy for PD. For enhancing dopamine production, the candidate genes are tyrosine hydroxylase, AADC and/or GTP cyclohydroxylase I. The second approach is a neuroprotective strategy, which is based on the usage of genes for neurotophic factors or anti-apoptotic agents. We also showed that Apaf-1-dominant negative inhibitor delivery using an AAV vector system could prevent nigrostriatal degeneration in MPTP mice, suggesting that it might be an anti-mitochondrial apoptotic gene therapy for PD. In 2003, the first gene therapy trial for PD performed at New York Weill Cornell Medical Center. The treatment is designed to deliver glutamic acid decarboxylase (GAD), the gene responsible for making GABA, into the subthalamic nucleus to "quiet down" that nucleus and alleviate Parkinson's symptoms. The last approach is replacement of disease for autosomal recessive PD. Because autosomal recessive juvenile parkinsonism (ARJP) involves the loss of function of parkin gene, gene therapy employing the parkin gene may prevent nigral cell death.
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PMID:[Future of gene therapy for Parkinson's disease]. 1565 40

Changes in cellular activity in the subthalamic nucleus are a cardinal feature of Parkinson's disease and occur in rodents after lesions of the nigrostriatal pathway, a model of Parkinson's disease. GABA-ergic neurons from the globus pallidus provide a major input to the subthalamic nucleus. Previous electrophysiological studies revealed temporal changes in the activity of pallidal neurons after nigrostriatal lesions in rats. However, little is known about the impact of these changes on GABAergic transmission in the subthalamic nucleus. We have examined the behavioral responses to a local administration of the GABA A agonist muscimol into the subthalamic nucleus. Muscimol (0.01 and 0.1 microg) induced orofacial dyskinesia in normal rats; this response was blunted 2 weeks but enhanced 2 months after a unilateral lesion of the nigrostriatal pathway. The early decrease in the behavioral response occurred at a time when increased expression of mRNA for glutamic acid decarboxylase, the enzyme of GABA synthesis, and burst firing have been reported in the globus pallidus, suggesting an adaptive post-synaptic response to increased GABAergic transmission in the subthalamic nucleus. In contrast, we now show that glutamic acid decarboxylase mRNA is unchanged in the globus pallidus at the later time point, when electrophysiological changes also subside in this region. The increased behavioral response at this later time point may reflect a decreased activity in GABAergic inputs to the subthalamic nucleus. The results show time-dependent changes in behavioral responses to GABA A receptor stimulation in the subthalamic nucleus which may reflect adaptive changes in postsynaptic inhibitory responses after dopaminergic lesions.
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PMID:Behavioral responses to injections of muscimol into the subthalamic nucleus: temporal changes after nigrostriatal lesions. 1573 Aug 80

Current evidence suggests that behavioral sensitization to the chronic administration of levodopa (L-DOPA) to dopamine-depleted animals involves a plasticity of GABA-mediated signaling in output regions of the basal ganglia. The purpose of this study was to compare in adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion the effects of an acute or chronic (for 3 or 7 days) injection of L-DOPA on mRNA levels encoding for glutamic acid decarboxylase (GAD65 and GAD67) in the striatum and GABA(A) receptor alpha1, beta2 and gamma2 subunits in the substantia nigra, pars reticulata (SNr), by in situ hybridization histochemistry. In addition, immunostaining levels for the alpha1 subunit were examined in the SNr. In agreement with previous studies, we found that L-DOPA administration increased GAD mRNA levels in the striatum of 6-OHDA-lesioned rats. However, the magnitude of this effect increased with the number of injections of L-DOPA. On the other hand, we found that 6-OHDA lesions resulted in increases in alpha1, beta2 and gamma2 mRNA levels in the ipsilateral SNr, which were normalized or decreased compared with the contralateral side by the acute or chronic administration of L-DOPA. In addition, alpha1 immunostaining in the SNr was significantly decreased in rats injected for 7 days but not for 3 days or acutely with L-DOPA. Our results demonstrate that a chronic administration of L-DOPA results in a progressive increase in GAD and decrease in GABA(A) receptor expression in the striatum and SNr, respectively. They provide further evidence that behavioral sensitization and dyskinesia induced by a chronic administration of L-DOPA in an experimental model of Parkinson's disease is paralleled by a plasticity of GABA-mediated signaling in the SNr.
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PMID:Comparative effects of acute or chronic administration of levodopa to 6-hydroxydopamine-lesioned rats on the expression of glutamic acid decarboxylase in the neostriatum and GABAA receptors subunits in the substantia nigra, pars reticulata. 1583 43

Marked fluctuation of dopamine concentration in the striatum following long-term L-DOPA administration contributes to the development of L-DOPA-induced motor complications including L-DOPA-induced dyskinesias and wearing-off in patients with Parkinson's disease. We have shown that pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A (5-hydroxytryptamine) receptor agonist, alleviates fluctuation of dopamine levels in the dopamine-denervated striatum of 6-hydroxydopamine-lesioned (hemiparkinsonian) rats after L-DOPA treatment. To determine whether co-administration of 8-OH-DPAT with L-DOPA prevents L-DOPA-induced motor complications, we examined rotation behavior and levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the striatum of 6-hydroxydopamine-lesioned rats treated with L-DOPA alone or L-DOPA + 8-OH-DPAT, twice daily, for 2 weeks. Co-administration of 8-OH-DPAT inhibited an increase of rotation behavior to L-DOPA and L-DOPA-induced increases in levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the dopamine-denervated striatum, both of which are established indices of L-DOPA-induced motor complications. These results suggest that pharmaceutical products that stimulate 5-HT1A receptors could prove useful in prevention of the development of L-DOPA-induced motor complications in patients with Parkinson's disease.
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PMID:A serotonin 5-HT1A receptor agonist prevents behavioral sensitization to L-DOPA in a rodent model of Parkinson's disease. 1589 79

Vectors derived from human foamy virus (HFV), with their nonpathogenic nature and a wide tissue tropism, have been successfully used as retroviral gene transfer vehicles. However, transduction of primary hippocampal neurons (HNs) with HFV vectors has little been studied. To investigate the potential of HFV-derived vector in gene therapy for neurological diseases, efficient foreign gene expression in cultured rat HNs was first demonstrated by successful enhanced green fluorescent protein (EGFP) transduction through a HFV vector bearing an EGFP expression cassette. Furthermore, we tested the effect on HNs that were transduced by a novel HFV vector expressing the human glutamic acid decarboxylase (GAD) cDNA, a therapeutic gene for neurological disorders such as epilepsy and Parkinson's disease. The transduced HNs showed significant increase in isoform-specific expression of GAD, synthesis of gamma-aminobutyric acid (GABA) and stimulation-evoked GABA release. These findings indicated for the first time that cultured rat HNs could be efficiently transduced by HFV vectors, and the GAD-expressing HFV vector has potential therapeutic value in the treatment of neurological diseases.
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PMID:Efficient therapeutic gene expression in cultured rat hippocampal neurons mediated by human foamy virus vectors: a potential for the treatment of neurological diseases. 1595 1

Few neurological diseases have received as much attention and investment in research as Parkinson's disease. Although great strides have been made in the development of agents to treat this neurodegenerative disease, none yet address the underlying problem associated with it, the progressive loss of dopaminergic neurons. Current therapeutic strategies for Parkinson's disease focus primarily on reducing the severity of its symptoms using dopaminergic medications. Although providing substantial benefit, these agents are burdened by adverse effects and long-term complications. This review highlights new and emerging therapies for Parkinson's disease, categorised as symptomatic, neuroprotective and neurorestorative, although at times, this distinction is not easily made. Novel symptomatic treatments target nondopaminergic areas in the hope of avoiding the motor complications seen with dopaminergic therapies. Two emerging treatment approaches under investigation are adenosine A(2A) receptor antagonists (such as istradefylline [KW-6002]) and glutamate AMPA receptor antagonists (such as talampanel [LY-300164]). In 2003, the results from two studies using istradefylline in patients with Parkinson's disease were published, with both showing a positive benefit of the study drug when used as adjunctive therapy to levodopa. In non-human primate models of Parkinson's disease, talampanel has been found to have antiparkinsonian effects when administered as high-dose monotherapy and antidyskinetic effects on levodopa-induced dyskinesias. NS-2330, another drug currently undergoing clinical trials, is a triple monoamine reuptake inhibitor that has therapeutic potential in both Parkinson's and Alzheimer's disease. A phase II proof-of-concept study is currently underway in early Parkinson's disease. However, a recently published study in advanced Parkinson's disease showed no therapeutic benefit of NS-2330 in this patient population. Even more exciting are agents that have a neuroprotective or neurorestorative role. These therapies aim to prevent disease progression by targeting the mechanisms involved in the pathogenesis of Parkinson's disease. Several lines of investigation for neuroprotective therapies have been taken, including the antioxidant coenzyme Q10 (ubidecarenone) and anti-apoptotic agents such as CEP-1347. Studies in patients with Parkinson's disease with coenzyme Q10 have suggested that it slows down functional decline. The PRECEPT study is currently in progress to assess the neuroprotective role of CEP-1347 in the early phase of the disease. Gene therapy is another exciting arena and includes both potentially neuroprotective and neurorestorative agents. Novel methods include subthalamic glutamic acid decarboxylase gene therapy and the use of glial cell line-derived neurotrophic factor (GDNF). Eleven of 12 patients have been enrolled in the first FDA-approved phase I subthalamic glutamic acid decarboxylase gene therapy trial for Parkinson's disease, with currently no evidence of adverse events. GDNF delivered intracerebroventricularly was studied in a small population of patients with Parkinson's disease, but unfortunately did not reveal positive results. Other methods of administering GDNF include direct delivery via infusions into the basal ganglia and the use of viral vectors; thus far, these approaches have shown promising results. This is an exciting and rewarding time for research into Parkinson's disease. With so many therapies currently under investigation, the time is ripe for the beginning of a new phase of treatment strategies.
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PMID:Treatment of Parkinson's disease : what's on the horizon? 1614 89

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