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)

Saccadic eye tracking was studied in a monkey given i.v. injections of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The Parkinson-like symptoms which appeared in the animal's general motor behavior (akinesia, bradykinesia, hypokinesia) were also observed in its eye tracking. Similar oculomotor deficits are seen in patients with idiopathic Parkinsonism. The MPTP model offers excellent possibilities for studying the mechanisms underlying the motor disabilities of Parkinson's disease.
 ...
PMID:Saccadic eye movement deficits in the MPTP monkey model of Parkinson's disease. 302 Dec 80

MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits selective destruction of nigrostriatal dopamine neurons in humans and animals along with clinical symptoms of parkinsonism. Recent studies clarify mechanisms accounting for this neurotoxicity. MPTP binds with high affinity to monoamine oxidase, which transforms it to the pyridinium MPP+ . MPP+ is selectively concentrated by the dopamine neuronal uptake system. In nigral cells, binding by melanin of MPP+ affords a "depot" release mechanism to maintain prolonged high intracellular concentrations sufficient to destroy cells. PC-12 cells provide a model catecholamine cell culture for screening environmentally occurring substances that may be relevant in the etiology of idiopathic Parkinson's disease.
 ...
PMID:MPTP: a neurotoxin relevant to the pathophysiology of Parkinson's disease. The 1985 George C. Cotzias lecture. 308 Jun 96

C57 black mice were injected repeatedly with maximal tolerated doses of 2 chemical analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 4-phenylpyridine and 4-phenyl-1,2,3,6-tetrahydropyridine. Although both compounds were clearly acutely toxic to mice, neither caused any reduction in striatal dopamine content after chronic exposure. Two MPTP analogues which may be formed endogenously during the metabolism of brain monoamines, 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydro-beta-carboline, were injected repeatedly into common marmosets. Again, although both compounds appeared highly toxic, neither caused any reduction in striatal dopamine content. It appears unlikely that any of these 4 MPTP analogues causes idiopathic Parkinson's disease.
 ...
PMID:4-phenylpyridine and three other analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lack dopaminergic nigrostriatal neurotoxicity in mice and marmosets. 310 59

Idiopathic Parkinson's disease (PD) may possibly be caused by one or more unidentified neurotoxins present in the environment, or formed endogenously, which progressively damage dopaminergic nigrostriatal neurons. N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an experimental neurotoxin which produces biochemical and neuropathological changes in humans, lower primates and mice that closely resemble those found in PD. Because the mechanisms of neuronal damage in both idiopathic PD and in the MPTP model of PD may involve free radical formation in the substantia nigra, antioxidants might protect dopaminergic neurons. Previously, we found that both alpha-tocopherol and beta-carotene partially protected mice against MPTP. However, in the experiments described in this paper, neither alpha-tocopherol nor beta-carotene, each administered in massive doses, had any demonstrable protective effect for dopaminergic nigrostriatal neurons in marmosets injected with low doses of MPTP. Without more knowledge about the identity of the neurotoxin(s) causing idiopathic PD, and their mechanism of action, it is not possible at this time to predict whether these 2 antioxidants might be clinically useful in preventing or ameliorating PD.
 ...
PMID:Alpha-tocopherol and beta-carotene do not protect marmosets against the dopaminergic neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 312

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause chronic Parkinsonism in humans, primates, and long lasting striatal dopamine depletion in mice. Acute animal models thus produced closely resemble Parkinson's disease. There are, however, two major differences. The one is a lack of Lewy bodies and the other is that norepinephrine system is relatively well preserved in the model. So the acute animal model is better considered a nigrostriatal dopamine deficiency model. We have produced another model by adding N-2-chloroethyl-N-ethyl-2-bromobenzyl-amine (DSP4) to MPTP. This material is known to produce selective destruction of norepinephrine terminal in the central nervous system as well as in the periphery. Both norepinephrine system and dopamine system are severely depressed in this model, and the functional role of norepinephrine system was investigated by comparing two models. 90 male C57 black mice weighing 20-25 grams were used. MPTP (Aldrich) was dissolved in sterile distilled water with 5% ethanol solution. Experimental animals were divided into three groups. i) control group; in this group animals received vehicles alone. ii) MPTP group; in this group, mice received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days, thus total doses of MPTP was 300 mg/kg. iii) MPTP & DSP4 group; in this group animals received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days and at the last day of MPTP injection they received DSP4 50 mg/kg i.p.. 7 to 14 days after the last injection of MPTP both treated and control mice received an intraperitoneal injection of L-DOPA (200 mg/kg & aromatic L-amino acid decarboxylase mg/kg) and the effect of this drug on three groups were investigated by using behavioral, biochemical and histofluorescence method. Histofluorescence studies by GA-FAS method revealed severe reduction of nigrostriatal dopamine in MPTP treated mice. Mesolimbic and mesocortical dopamine systems seemed relatively preserved. There was no apparent changes in locus coeruleus norepinephrine system. In MPTP & DSP4 treated mice marked reduction of norepinephrine terminal fluorescence as well as nigrostriatal dopamine system was observed. Chemical analysis of norepinephrine and dopamine by HPLC confirmed histofluorescence studies. Behavioral studies were analyzed by Automex locomotor activity meter. Marked increase of locomotor activity was observed in MPTP treated mice after L-DOPA administration.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:[A mouse model of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism: effect of norepinephrine terminal destruction]. 331 16

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent dopaminergic neurotoxin, was administered to cats systemically for 5 to 7 days. This treatment produced a behavioral syndrome characterized by akinesia, ataxia, bradykinesia, and feeding difficulties, lasting for several weeks. During this period of severe behavioral impairment, caudate and nucleus accumbens dopamine and norepinephrine concentrations were quite depleted. Behavioral recovery ensued over the next several weeks as did some recovery of striatal catecholamines. MPTP destroyed the majority of substantia nigra pars compacta neurons while affecting a much lesser number of locus ceruleus and ventral tegmental neurons. These results demonstrated for the first time that MPTP can cause long-lasting deficits in nigrostriatal functioning in the cat and may provide a means for studying the apparently selective neurotoxic effects of MPTP as well as for understanding the pathophysiology of Parkinson's disease.
 ...
PMID:Production of a Parkinson-like syndrome in the cat with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): behavior, histology, and biochemistry. 348 7

Idiopathic Parkinson's disease (PD) has been reported to occur more commonly among non-smokers than among cigarette smokers, for reasons that are unknown. PD may possibly be caused by one or more unidentified neurotoxins which chemically resemble N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a substance which after conversion to an active neurotoxin by monoamine oxidase B (MAO-B) can extensively damage dopaminergic nigrostriatal neurons in humans, lower primates and mice. We measured MAO-B in autopsied brain of PD patients and control subjects and found enzyme activities similar. Inhibition of rat liver MAO-B by the urines of PD patients was greater than by urines of control subjects. These observations do not favour the hypothesis that idiopathic PD is due to excessive conversion of a precursor compound to an active neurotoxin by MAO-B. On the other hand, we found that MAO-B activity was significantly lower in the platelets of heavy cigarette smokers than in platelets of non-smokers. Finally, we found that hydrazine, a compound present in tobacco smoke, had a significant effect in mice in protecting dopaminergic nigrostriatal neurons from damage by MPTP. If idiopathic PD is caused by MPTP-like neurotoxins, accumulation of hydrazine in the tissues of cigarette smokers might explain their reduced likelihood of developing PD.
 ...
PMID:Monoamine oxidase B, smoking, and Parkinson's disease. 348 45

C57 black mice were injected repeatedly with maximal tolerated doses of 4 different chemical analogues of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or its metabolite N-methyl-4-phenylpyridinium ion (MPP+), in order to assess their possible neurotoxicity for dopaminergic nigrostriatal neurons and their potential for causing idiopathic Parkinson's disease. The 4 analogues were the herbicide paraquat, reduced paraquat (having two N-methyl-tetrahydropyridine moieties), N-methyl-1,2,3,4-tetrahydroisoquinoline, and 2-methyl-1,2,3,4-tetrahydro-beta-carboline, the latter two compounds being possible endogenous neurotoxins. Contents of striatal dopamine, measured by high-performance liquid chromatography with electrochemical detection one month after injections were completed, were not depleted by any of these 4 compounds in mice. They might conceivably prove more neurotoxic in primates.
 ...
PMID:Paraquat and two endogenous analogues of the neurotoxic substance N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine do not damage dopaminergic nigrostriatal neurons in the mouse. 348 12

The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce degeneration of dopamine (DA) and other central monoamine neurons, leading to Parkinson's disease-like effects in man, monkey, and mouse. MPTP and other substituted phenylpiperidines related to synthetic analgesics including alphaprodine and meperidine were evaluated for potency vs. uptake of 0.1 microM tritiated DA, norepinephrine (NE), or serotonin (5HT) in synaptosomal preparations of mouse striatum or cerebral cortex. The most potent inhibitor of the uptake of 3H-DA was N-methyl-4-phenylpyridinium ion (MPP+; IC50 = 1 microM, Ki = 0.4 microM), a metabolite of MPTP; its effect was competitive and reversible. Other analogs of MPTP: the N-ethylindole AHR-1709, N,N-dimethyl-MPTP, and N-methyl-4-phenylpiperidine were all more potent than MPTP against 3H-DA uptake. N-dealkylation and N-propyl substitution, as well as pyridine ring substitution, decreased affinity for DA uptake while 3',4'-dihydroxyphenyl substitution increased potency and selectivity for catecholamine uptake, and quarternarization of the pyridine ring also increased potency against DA uptake. Active compounds showed higher potency against the uptake of NE than of DA. MPP+ was also more potent than MPTP in releasing endogenous DA from striatal synaptosomes (EC50 = 3 vs. 30 microM), but did not release the cytoplasmic markers tyrosine hydroxylase and lactate dehydrogenase (LDH). In contrast to MPTP, synthetic phenylpiperidine analgesics, their potential metabolites and the experimental neuroleptic agent AHR-1709 all failed to deplete striatal DA in vivo, even if active in vitro against DA uptake.
 ...
PMID:Synthetic analgesics and other phenylpiperidines: effects on uptake and storage of dopamine and other monoamines mouse forebrain tissue. 349 Jun 12

Epidemiological surveys have repeatedly shown that idiopathic Parkinson's disease (PD) occurs less frequently in persons who have smoked cigarettes for many years than among age-matched non-smokers. Since PD might be caused by neurotoxins chemically similar to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we explored the possible protective effect of repeated exposure to cigarette smoke against MPTP neurotoxicity in the C57 black mouse. Mice given MPTP and exposed to cigarette smoke suffered just as great a depletion of striatal dopamine as did mice treated only with MPTP. We discovered also that different lots of C57 black mice obtained from a single supplier can have markedly different sensitivities to MPTP.
 ...
PMID:Exposure to cigarette smoke does not decrease the neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. 349 63


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