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)

MPTP administration induces a fairly selective lesion of substantia nigra dopaminergic neurons both in animals and humans. This characteristic of MPTP has led to the best available model of Parkinson's disease and neuronal degenerations. MPTP toxicity is actually provoked by MPP+ which results after oxidation by MAO-B. Possible mechanism of action of MPP+ include: 1) Mitochondrial lesion. 2) Free radicals generation. 3) Trapping of MPP+ by highly melanized neurons. This article reviews the mechanisms of toxicity by MPTP and its neuropathological characteristics.
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PMID:[Experimental model of Parkinson disease: mechanisms and anatomo- pathological characteristics of MPTP neurotoxicity]. 141 23

Epidemiologic evidence of an inverse relationship between cigarette smoking and Parkinson's disease suggests that a component of cigarette smoke protects against nigrostriatal degeneration. Nicotine, a major component of cigarette smoke, is similar in chemical structure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and is metabolized in part by the same enzymes that detoxify MPTP. We investigated the effect of chronic nicotine on MPTP neurotoxicity in two strains of mice and found that nicotine increases rather than decreases MPTP toxicity. These results are not compatible with the hypothesis that nicotine is that component of cigarette smoke that protects against nigrostriatal degeneration, at least in the MPTP experimental model of Parkinson's disease.
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PMID:Nicotine enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. 144 1

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes selective destruction of nigrostriatal dopaminergic neurons in primates, giving rise to a condition resembling Parkinson's disease. The toxicity of MPTP is believed to be due to its metabolite 1-methyl-4-phenylpyridinium (MPP+). MPP+ is an inhibitor of mitochondrial respiration at the NADH-ubiquinone oxidoreductase site and this, together with its selective transport into dopaminergic nerve terminals, accounts for its neurotoxicity. In this paper an electrode selective for MPP+ was developed and used to measure the rate of uptake and the steady-state accumulation of MPP+ in rat liver mitochondria. The initial rates of MPP+ uptake were not saturable, confirming previous work that the transport of MPP+ is not carrier-mediated. The membrane potential of mitochondria respiring on succinate was decreased by MPP+ and the steady-state accumulation ratio of MPP+ did not come to equilibrium with the mitochondrial transmembrane potential gradient (delta psi). The effect of the cation exchanger tetraphenylboron (5 microM) was to increase the initial rate of MPP+ uptake by about 20-fold and the steady-state accumulation by about 2-fold. This suggests that there may be a mechanism of efflux of MPP+ from mitochondria which allows MPP+ to cycle across the membrane and thus decrease delta psi. These data indicate that MPP+ interacts with mitochondria independently of its inhibition of NADH-ubiquinone oxidoreductase, and these alternative interactions may be of relevance for its mechanism of neurotoxicity.
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PMID:Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode. 146 48

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood. Using this technique, we analyzed respiratory chain function in 25 patients with PD and 15 matched control subjects. We confirm a previous report of a specific complex I deficiency in PD platelet mitochondria. Although there was a statistically significant decrease in complex I activity in the PD group compared with the control group (p = 0.005), the defect was mild (16%); it was not possible to distinguish PD from control values on an individual basis. This deficiency is not detectable in platelet whole-cell homogenates, presumably reflecting the relative insensitivity of this preparation and the limited decrease in complex I activity in PD. The presence of a mild complex I defect in platelets together with a more severe defect in substantia nigra suggests either that the pharmacological characteristics shared by these two tissues render them susceptible to a particular toxin or toxins, or that the defect is widely distributed and other biochemical events enhance the deficiency in substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group. 147 69

Oxidant stress, due to the formation of hydrogen peroxide and oxygen-derived free radicals, can cause cell damage due to chain reactions of membrane lipid peroxidation. Because the substantia nigra is rich in dopamine, which can undergo both enzymatic oxidation via monoamine oxidase and nonenzymatic autoxidation, hydrogen peroxide and oxyradicals (superoxide anion radical and hydroxyl radical) are generated in this midbrain nucleus. Although proof that oxidant stress actually causes the loss of monoaminergic neurons in patients with Parkinson's disease is lacking, there is a considerable body of evidence from studies in both animals and humans that support the concept. (1) Neurotoxins that selectively destroy the dopaminergic neurons in the nigra, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), appear to act via oxidant stress. (2) The substantia nigra of patients with Parkinson's disease reveals evidence of oxidant stress by the findings of increased lipid peroxidation and decreased reduced glutathione. (3) Total iron is increased and ferritin is reduced in the substantia nigra pars compacta in patients with Parkinson's disease. This combination suggests that this transition metal is in a low molecular weight form, capable of catalyzing nonenzymatic oxidative reactions, especially the conversion of hydrogen peroxide to hydroxyl radical, which is the most reactive of the oxygen radicals. (4) Neuromelanin, a product of dopamine autoxidation, can serve as a reservoir for iron, promoting the generation of oxyradicals. (5) Antioxidant defense mechanisms appear to be reduced in the parkinsonian substantia nigra with the findings of decreased activities of glutathione peroxidase and catalase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. 147 73

The first paper on the beneficial effect of selegiline in the treatment of Parkinson's disease was published 17 years ago. In the first ten years several clinical studies were conducted world-wide to prove its efficacy as an adjuvant to the basic 1-dopa therapy. Although the design, duration and number of treated patients were different, the overall results were mainly uniform. The patients treated with 1-dopa selegiline combination showed marked improvement in disability, increasing duration of 1-dopa effect and marked lessening of dose-related fluctuations were seen, compared to those treated with 1-dopa alone. It became also generally evident that selegiline allows a 10-30% decrease in 1-dopa dose. The investigations in which selegiline has been used as monotherapy have been triggered by some purely clinical experience and by the discovery of pathobiochemical mechanisms of MPTP toxicity which causes fairly similar clinical picture to Parkinson's disease and can be successfully prevented by selegiline. The newly diagnosed parkinsonian patients treated with selegiline alone showed marked improvement in their clinical state. Beside the actual clinical effect on disability, selegiline slowed down the progression of Parkinson's disease. The latter fact has been proven in the largest clinical trial ever done with selegiline (DATATOP). Selegiline monotherapy can delay the need for 1-dopa substitution by around one year or longer. Based on the continuously growing clinical experiences it became widely accepted that selegiline is the drug of choice as initial treatment for newly diagnosed parkinsonian patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:["Widening horizons" in the clinical application of selegiline]. 148 11

Advance in understanding of the anatomy, physiology and pharmacology of basal ganglia organisation over the past decade revealed a functional relation between excitatory glutamatergic and the degenerated dopaminergic nigrostriatal transmitter systems which could serve as targets for pharmacological interventions in Parkinson's disease. The selective AMPA-antagonist NBQX is not effective in animal models of Parkinson's disease when given alone but ameliorates parkinsonian symptomatology and enhances the locomotor response of a threshold dose of L-DOPA. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Here we report that, in the latter model, such synergism of NBQX is also seen with the direct dopamine agonists lisuride and apomorphine, indicating the potential usefulness of AMPA antagonists for the symptomatic treatment of Parkinson's disease.
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PMID:Synergism of NBQX with dopamine agonists in the 6-OHDA rat model of Parkinson's disease. 149 Dec 48

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to dogs produces clinical, pathological and neurological features in dog resembling human Parkinson's disease. Using this animal model, we studied the changes in diurnal rhythms of urine volume, creatinine in urine, and vasopressin, aldosterone and renin activity in plasma. Before MPTP treatment, urine volume showed a peak between 17.00 and 1.00 and plasma vasopressin concentration also showed a clear circadian rhythm with a peak at 13.00 and a minimum level at 5.00. Two weeks after MPTP treatment (2.5 mg/kg i.v.), the rhythm of urine volume disappeared and that of vasopressin became less clear. Plasma renin activity increased 2 and 4 weeks after MPTP treatment. The increase was, however, not enough to change the concentration of plasma aldosterone. We examined the effect of L-3,4-dihydroxyphenylalanine (levodopa), on the circadian pattern of urine volume and vasopressin attenuated by MPTP. Levodopa (4 mg/kg/day) was administered orally every day from the first week after MPTP treatment. The circadian rhythms of urine volume and vasopressin reappeared within one week after the start of levodopa administration.
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PMID:Disappearance of circadian rhythms in Parkinson's disease model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in dogs. 150 21

Male retired breeder C57/Bl and CD-1 mice were treated with either MPTP or its vehicle. At 7-10 days post-treatment, catecholamine concentrations within the olfactory bulbs (OB) and hypothalamus were determined. Norepinephrine concentrations within the OB were significantly decreased in MPTP-treated mice. These effects were more pronounced in the CD-1 (50% reduction) compared to the C57/Bl (20% reduction) strain. No effects of MPTP were observed on norepinephrine concentrations within the hypothalamus. Dopamine concentrations in the OB and hypothalamus did not differ between MPTP- and vehicle-treated mice in either strain. Overall, catecholamine concentrations within the OB, but not the hypothalamus, were significantly greater in C57/Bl compared to CD-1 mice. The reduction in OB norepinephrine concentration in the MPTP-treated animals may be related to the olfactory deficits which accompany Parkinson's disease.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduces norepinephrine concentrations in the olfactory bulbs of male mice. 151 43

Evidence exists for a negative correlation between Parkinson's disease and smoking. The present and previous studies indicate that nicotine treatment can markedly alter the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in the black mouse based on biochemical determinations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in neostriatum and substantia nigra 2 weeks after MPTP injection. Acute intermittent treatment with (-)nicotine starting 10 min before the MPTP injection partly protected against MPTP-induced neurotoxicity in the neostriatum and substantia nigra. Also, a partial protection was observed in the substantia nigra when (-)nicotine was given together with MPTP in an acute intermittent treatment schedule. Conversely, chronic infusion of (-)nicotine via minipumps produced a dose-related enhancement of MPTP-induced DA neurotoxicity in the neostriatum. It is suggested that the protective activity of nicotine in the MPTP model is related to a blockade of MPP+ uptake into the DA cells via increased DA release. Conversely, the nicotine enhancement of MPTP-induced DA toxicity is suggested to be caused by a failure of the nicotinic cholinoceptors to desensitize to the chronic (-)nicotine exposure, leading to increased chronic influx of Na+ and Ca2+ ions via the ion channels of the nicotinic cholinoceptors located on the DA neurons with associated increased Ca ion toxicity and increased energy demands.
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PMID:Differential effects of acute and chronic nicotine treatment on MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced degeneration of nigrostriatal dopamine neurons in the black mouse. 152 Oct 37


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