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)

We investigated whether excitatory amino acids acting at the N-methyl-D-aspartate (NMDA) subtype of the L-glutamate receptor contribute to the dopaminergic neurotoxicity induced by systemic administration of the Parkinson's syndrome-inducing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl/6 mice. The MPTP-regimen chosen (30-40 mg/kg body weight subcutaneously) resulted a 60-70% depletion of striatal dopamine (DA) content and a 20% reduction of tyrosine hydroxylase immunoreactive (TH-IR) cells in the substantia nigra pars compacta 20 days after administration. Repeated systemic coadministration of the non-competitive NMDA receptor antagonist MK-801 or of the novel competitive NMDA receptor antagonist CGP 40116 did not protect against MPTP-induced striatal DA depletion 20 days after toxin administration. Additionally, no short-term protective effects of MK-801 on striatal DA content were observed 24, 48, and 96 h, respectively, after exposure to MPTP. A slight and non-significant attenuation (approximately 10%) of the MPTP-induced decrease in the number of nigral TH-IR cells was observed after MK-801- and CGP 40116-treatment. We conclude that neurotoxicity of systemically administered MPTP is not substantially antagonized by NMDA receptor antagonists in mice.
 ...
PMID:Do NMDA receptor antagonists protect against MPTP-toxicity? Biochemical and immunocytochemical analyses in black mice. 136 Mar 17

The effect of arotinolol, a peripherally acting beta-adrenergic-blocking agent, on postural or kinetic tremor was studied in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Male cynomolgus monkeys (Macaca fascicularis) were treated with three injections of MPTP hydrochloride (0.3 mg/kg, i.v.) at an interval of 3-4 days, followed by several injections of the same dose every 7 days. Four monkeys with persistent parkinsonian symptoms manifested for greater than 1 year were used. The animals developed mild to moderate degrees of postural or kinetic tremor, and their motor activity was reduced. Arotinolol (20-30 mg/kg, s.c.) significantly suppressed postural tremor in a dose-dependent manner. Propranolol (20-30 mg/kg) was also effective in suppressing the tremor. However, the application of propranolol induced emesis, whereas arotinolol had no adverse effects. These results suggest that arotinolol is a useful adjunct to dopaminergic therapy for tremor in Parkinson's disease.
 ...
PMID:Therapeutic effects of arotinolol, a beta-adrenergic blocker, on tremor in MPTP-induced parkinsonian monkeys. 138 70

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.
 ...
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.
 ...
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)
 ...
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)
 ...
PMID:The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. 147 73

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.
 ...
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.
 ...
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

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.
 ...
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

The meperidine analogue derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal fiber damage and severe parkinsonism in humans and animals. MPTP-induced parkinsonism has been proposed as a model of Parkinson disease, but doubts have been raised about whether the patterns of nigrostriatal fiber loss in the two conditions are similar. We report here observations on [3H]mazindol monoamine (principally dopamine) uptake-site binding in the striatum of monkeys (Saimiri sciureus) exposed to low doses of MPTP. We show that this treatment can produce a pattern of nigrostriatal degeneration characteristic of that seen in Parkinson disease, in which there is greater depletion of dopaminergic markers in the putamen than in the caudate nucleus, especially posteriorly. Moreover, within the regions of diminished uptake-site binding in the MPTP-treated monkeys, there is differential preservation of binding in striosomes relative to the surrounding matrix. We suggest that both regional and striosome/matrix patterns of nigrostriatal depletion are key features of MPTP-induced neurodegeneration and that both patterns may provide clues to the mechanisms underlying neurodegeneration in Parkinson disease as well.
 ...
PMID:Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 157 Mar 4


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>