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

Because there is biochemical evidence of decreased GABAergic function in Parkinson's disease, sodium valproate, an inhibitor of GABA catabolism, was administered to eight Parkinsonian patients. Valproate treatment did not significantly alter any Parkinsonian feature, but tended to increase the dyskinesia in the "on-off" patients. The increased dyskinesias were not a result of altered peripheral metabolism of L-dopa. Despite obtaining high plasma levels of valproate, no consistent alteration of CSF GABA levels could be demonstrated. Thus, in these patients, an effect of valproate on GABA metabolism is unproven, and in turn, the role of GABA in Parkinsonism and dyskinesia uncertain.
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PMID:Treatment of Parkinson's disease with sodium valproate: clinical, pharmacological, and biochemical observations. 38 31

This randomized, double-blind trial was designed to evaluate the efficacy of a transdermal system of piribedil on the motor symptoms of Parkinson's disease during 3 weeks of treatment administered to three different groups: placebo, one piribedil patch (1 PP), and two (2 PP) piribedil patches. Twenty-seven patients with idiopathic Parkinson's disease, treated with L-dopa but not sufficiently controlled, were included in this trial. The test treatment did not demonstrate any clinical efficacy on either the main end point (Unified Parkinson's Disease Rating Scale motor score) or the secondary end points (rigidity, bradykinesia, postural, and resting tremor scores). The main adverse events were nausea (11%), vomiting (7.4%), and malaise (7.4%) mainly observed in the placebo group (four of seven patients). The local acceptability of the transdermal system was good. Plasma piribedil concentrations at the end of treatment were 6.74+/-1.10 and 9.31+/-3.33 ng/mL in the 1 PP and 2 PP groups, respectively. These plasma levels could account for the lack of clinical efficacy, because a previous pharmacokinetics-PD study conducted in parkinsonian patients and treated with the intravenous route demonstrated that the critical limits of activity on tremor were between 10 and 30 ng/mL.
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PMID:A randomized, double-blind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson's disease. 1009 30

Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Accumulating evidence supports the notion that neuroinflammation is involved in the pathogenesis of this disease. Valproate (VPA) has long been used for the treatment of seizures and bipolar mood disorder. In vivo and in vitro studies have demonstrated that VPA has neuroprotective and neurotrophic actions. In this study, using primary neuron-glia cultures from rat midbrain, we demonstrated that VPA is a potent neuroprotective agent against lipopolysaccharide (LPS)-induced neurotoxicity. Results showed that pretreatment with 0.6 mM VPA for 48 h robustly attenuated LPS-induced degeneration of dopaminergic neurons as determined by [(3)H] dopamine uptake and counting of the number of TH-ir neurons. The neuroprotective effect of VPA was concentration-dependent and was mediated, at least in part, through a decrease in levels of pro-inflammatory factors released from activated microglia. Specifically, LPS-induced increase in the release of TNFa, NO, and intracellular reactive oxygen species was markedly reduced in cultures pretreated with VPA. These anti-inflammatory effects of VPA were time and concentration-dependent correlated with a decrease in the number of microglia. Thus, our results demonstrate that protracted VPA pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity through a reduction in levels of released pro-inflammatory factors, and further suggest that these anti-inflammatory effects may be contributed by VPA-induced reduction of microglia cell number. Taken together, our study reinforces the view that VPA may have utility in treating Parkinson's disease.
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PMID:Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. 1579 May 40

Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.
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PMID:Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. 1696 67

Calcium plays important roles in various cellular processes. Using transmitochondrial hybrid cells (cybrids) carrying fluorescent calcium indicators, we previously found two mitochondrial DNA (mtDNA) polymorphism sites, 8701 and 10398, that alter intracellular calcium signalling and mitochondrial pH. The 10398A polymorphism is reportedly associated with bipolar disorder, Parkinson's disease, Alzheimer's disease, and cancer, whereas 10398G is associated with longevity. In bipolar disorder, elevation of intracellular calcium levels in the platelets and lymphocytes is a well-replicated finding. Thus, we examined whether two mood stabilizers, lithium and valproate, affect the intracellular calcium signalling in cybrids with these mtDNA polymorphisms. After cybrids with 8701A/10398A and 8701G/10398G (three cell lines for each) derived from healthy controls were pretreated with lithium (0.75 mm or 1.5 mm) or valproate (0.6 mm or 1.2 mm) for 7 d, they were stimulated by 10 mum histamine. Valproate decreased mitochondrial calcium levels, compared with untreated cybrids, only in cybrids with 8701A/10398A. Moreover, valproate decreased cytosolic calcium levels at plateau after stimulation in cybrids with 8701A/10398A. These finding suggest that valproate may stabilize intracellular calcium only in cells with high mitochondrial calcium levels.
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PMID:Mitochondrial DNA-dependent effects of valproate on mitochondrial calcium levels in transmitochondrial cybrids. 1728 45

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease.
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PMID:Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. 1785 Sep 78

A prospective, randomized, double-blind pilot study to compare the results of stereotactic unilateral pallidotomy and subthalamotomy in advanced idiopathic Parkinson's disease (PD) refractory to medical treatment was designed. Ten consecutive patients (mean age, 58.4 +/- 6.8 years; 7 men, 3 women) with similar characteristics at the duration of disease (mean disease time, 8.4 +/- 3.5 years), disabling motor fluctuations (Hoehn & Yahr stage 3-5 in off-drug phases) and levodopa-induced dyskinesias were selected. All patients had bilateral symptoms and their levodopa equivalent dosing were analysed. Six patients were operated on in the globus pallidus interna (GPi) and four in the subthalamic nucleus (STN). Clinical evaluation included the use of the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn&Yahr score and Schwab England activities of daily living (ADL) score in 'on'- and 'off'-drug conditions before surgery and 6 months after surgery. There was statistically significant improvement in all contralateral major parkinsonian motor signs in all patients followed for 6 months. Levodopa equivalent daily intake was significantly reduced in the STN group. Changes in UPDRS, Hoehn & Yahr and Schwab England ADL scores were similar in both groups. Cognitive functions were unchanged in both groups. Complications were observed in two patients: one had a left homonymous hemianopsia after pallidotomy and another one developed left hemiballistic movements 3 days after subthalamotomy which partly improved within 1 month with Valproate 1000 mg/day. The findings of this study suggest that lesions of the unilateral STN and GPi are equally effective treatment for patients with advanced PD refractory to medical treatment.
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PMID:Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease. 1923 5

Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson's disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.
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PMID:Valproic acid is neuroprotective in the rotenone rat model of Parkinson's disease: involvement of alpha-synuclein. 1962 87

Little is known about comorbidities of bipolar disorder such as Parkinson's disease. A case history and a literature survey indicate that bipolar disorder is linked with or influences Parkinson's disease and vice versa. Underlying mechanisms are poorly understood, and, more importantly, no treatment options are established in such double diagnoses. The few data in comorbid Parkinson cases seem to point to a rapid cycling pattern of bipolar symptoms. With regard to therapeutic intervention, the literature supports pramipexole for treatment of both Parkinson and depressive symptoms in bipolar depression. Lithium, the mood stabilizer of choice for treating manic states, is problematical for use in Parkinson patients because of its side effects. Valproate might be an alternative, especially for treatment of rapid cycling.
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PMID:Bipolar affective disorder and Parkinson's disease. 2216 96

This open study was designed to evaluate the efficacy of valproate as a treatment for delirium and/or aggressive behavior in patients with dementia. Of the patients who participated, nine had vascular dementia, two had Alzheimer's disease, one had Parkinson's disease and one had alcohol dependence, all meeting DSM-IH-R criteria for dementia. In these 13 patients, delirium in seven and aggressive behavior in 12 patients were the target symptoms of this study. Valproate was administered orally at a dose of 200-600 mg daily (mean 526 mg, sd=20.4) without changing the dose of the other medications. The effect of valproate on delirium and aggressive behavior was evaluated with the Delirium Rating Scale (DRS) and Gottfries-Brane-Steen Scale (GBS). The total DRS scores decreased in 6/7 patients with delirium (P < 0.05) within 2 weeks. There were significant diferences between the score variances (before and during treatment) of the three categories in the GBS scale: emotional lability (P < 0.01), irritability (P < 0.01) and restlessness (P < 0.01). These findings suggest the effectiveness of valproate treatment for delirium and/or aggressive behavior in demented patients.
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PMID:Effectiveness of valproate on delirium and/or aggressive behavior in demented patients: A practical pilot study. 2494 45


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