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)

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is toxic to the nigrostriatal dopaminergic neurons and produces a syndrome similar to Parkinson's disease. Conversion of MPTP to 1-methyl-4-phenylpyridine (MPP+) by monoamine oxidase-B (MAO-B) appears necessary for this neurotoxicity. When MPTP was used as the substrate for the histochemical localization of monoamine oxidase activity on sections of the rat brain, only a few specific sites were found in which MPTP oxidation to MPP+ occurs. These include the noradrenergic and serotoninergic neurons of the brainstem and the histamine neurons of the caudal hypothalamus. Dopamine neurons themselves do not display the capacity to oxidize MPTP. It is proposed that the conversion of MPTP to MPP+ occurs via MAO-B within serotonin and histamine neurons which may innervate the substantia nigra where the toxin MPP+ could be released and then taken up into the dopamine neurons.
 ...
PMID:Histochemistry of MPTP oxidation in the rat brain: sites of synthesis of the parkinsonism-inducing toxin MPP+. 348 52

This study assessed the influence of aging on substantia nigra degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive neuronal degeneration was found in the substantia nigra of older (8-12 months of age) but not younger (6-8 weeks of age) mice given MPTP. Older mice did not have higher brain concentrations of either MPTP or 1-methyl-4-phenylpyridinium (MPP+), the putative toxic metabolite of MPTP, to account for the greater toxicity. In fact, older mice metabolized MPTP more rapidly than younger mice, probably because of the increase in monoamine oxidase activity that occurs with aging. Striatal synaptosomes from older mice did not accumulate more [3H]MPP+ than synaptosomes from younger mice. Thus, it is concluded that the greater neurodegenerative effect of MPTP in older animals is not due to greater levels or uptake of MPP+, but rather is related to a true increase in sensitivity of older dopaminergic cells to MPTP. For comparative purposes, the toxic effect of another dopaminergic neurotoxin, methamphetamine, was tested. Older animals were not more sensitive than young mature animals to the toxic effect of methamphetamine. This finding indicates that the increased sensitivity of older dopaminergic neurons to MPTP is selective. The link established here between aging and the neurodegenerative effect of MPTP, a toxin which produces parkinsonism in humans, provides a mechanism by which an age-related neurodegenerative disorder such as Parkinson's disease could be caused by an MPTP-like toxin in the environment.
 ...
PMID:Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra. 349 27

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and subhuman primates, but not in rats and many other laboratory animals; mice are intermediate in their susceptibility. Since MPTP causes selective dopaminergic neurotoxicity when infused directly into rat substantia nigra, we hypothesized that systemic MPTP may be metabolized by monoamine oxidase and/or other enzymes in rat brain capillaries and possibly other peripheral organs and thus prevented from reaching its neuronal sites of toxicity. We tested this hypothesis by assessing monoamine oxidase in isolated cerebral microvessels of humans, rats, and mice by measuring the specific binding of [3H]pargyline, an irreversible monoamine oxidase inhibitor, and by estimating the rates of MPTP and benzylamine oxidation. [3H]Pargyline binding to rat cerebral microvessels was about 10-fold higher than to human or mouse microvessels. Also, MPTP oxidation by rat brain microvessels was about 30-fold greater than by human microvessels; mouse microvessels yielded intermediate values. These results may explain, at least in part, the marked species differences in susceptibility to systemic MPTP. They also suggest the potential importance of "enzyme barriers" at the blood-brain interface that can metabolize toxins not excluded by structural barriers, and may provide biological bases for developing therapeutic strategies for the prevention of MPTP-induced neurotoxicity and other neurotoxic conditions including, possibly, Parkinson disease.
 ...
PMID:Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity. 349

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.
 ...
PMID:Chronic alterations in jejunal myoelectric activity in rats due to MPTP. 350 Dec 48

The chance occurrence of an outbreak of persistent parkinsonism amongst young drug addicts abusing a synthetic pethidine derivative has aroused considerable interest. The offending agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has to be converted by monoamine oxidase B perhaps in glia, into the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). MPP+ is then taken up into dopaminergic neurons by the normal dopamine re-uptake system. Once within dopaminergic neurons it binds to neuromelanin, so is retained to kill nerve cells, perhaps by generation of free radicals and other toxic species. MPTP produces parkinsonism in primates (but not in many lower species, probably because they possess little or no neuromelanin). MPTP toxicity in primates can be prevented by treatment with monoamine oxidase inhibitors, or by inhibitors of dopamine re-uptake, and to some extent by antioxidants. Toxicity of MPTP is remarkably selective. It preferentially destroys the substantia nigra pars compacta, but may spare the adjacent pigmented ventral tegmental areas, as well as other neuronal systems. However, selectivity decreases with age: MPTP causes more widespread damage in older animals. Affected individuals exhibit all symptoms and signs of Parkinson's disease. As well as providing an accurate animal model of the illness, MPTP is one of the first environmental neurotoxins known to cause parkinsonism in humans. This observation has led to reappraisal of the epidemiology of the illness and a search for similar environmental agents. Understanding the mechanism of MPTP toxicity has also provided suggestions on how to treat the cause of Parkinson's disease.
 ...
PMID:The significance of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 355 86

The experiments characterized the dose- and time-dependence of parkinsonian motor signs induced by reserpine in rats and a standardized system of manipulation of animals, evaluation of symptoms and analysis of data was devised. The assay procedure yielded no more than 0.5, 4.5 and 0.0% false positives with the evaluation of tremor, rigidity and hypokinesia, respectively. A dose-dependent and often complete blockade of all three signs was obtained with L-DOPA plus carbidopa (10:1) as well as with other classes of pharmacological agents that are used in the treatment of Parkinson's disease, i.e. direct or indirect dopamine (DA) agonists (amantadine, pergolide, lisuride) and inhibitors of monoamine oxidase (MAO) (clorgyline, pargyline, deprenyl, tranylcypromine). The inhibitor of the uptake of DA, nomifensine, and anticholinergics, 5-hydroxytryptamine (5-HT) antagonists, histamine antagonists and tricyclic antidepressants exerted little or no effect. The effects of putative agonists and antagonists at alpha 1- and alpha 2-adrenoceptors were also examined. Yohimbine blocked tremor and rigidity, but not hypokinesia, at 0.66 and 0.28 mg/kg, respectively. It is suggested that alpha-adrenergic mechanisms and, in particular, alpha 2-adrenoceptors, may be involved in reserpine-induced tremor and rigidity. Noradrenergic and dopaminergic systems can conceivably interact to progressively generate these different motor signs.
 ...
PMID:Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rat. 367 May 63

1-Methyl-4-phenyl-tetrahydropyridine (MPTP) given in single doses to rats depleted norepinephrine concentration in heart and mesenteric artery but had little effect on catecholamine concentration in brain. MPTP did not share with amphetamine the ability to cause persistent depletion of striatal dopamine in iprindole-treated rats. Administration of MPTP via osmotic minipumps implanted s.c. for 24 hrs after a loading dose of MPTP in rats resulted in depletion of striatal dopamine and its metabolites one week later. MPTP in vitro was a reasonably potent, competitive and reversible inhibitor of MAO-A (monoamine oxidase type A). MPTP appeared to inhibit MAO-A in rat brain in vivo as determined by its antagonism of the inactivation of MAO-A by pargyline and by its antagonism of the increase in dopamine metabolites resulting from the administration of Ro 4-1284, a dopamine releaser. The inhibition of MAO-B by MPTP in vitro was noncompetitive, time-dependent, and not fully reversed by dialysis, consistent with the findings of others that MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP given s.c. resulted in marked depletion of dopamine and its metabolites one week later, and the depletion of dopamine was completely prevented by pretreatment with deprenyl, which inhibited MAO-B but not MAO-A. These and other studies in rodents may help in elucidating the mechanisms involved in the destructive effects of MPTP on striatal dopamine neurons that lead to symptoms of Parkinson's disease in humans and in monkeys.
 ...
PMID:Central and peripheral catecholamine depletion by 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in rodents. 387 Dec 44

In the aging brain there is a loss of neurons compensated for by a proliferation of glial cells. Because of the increased B-type monoamine oxidase (MAO) activity present in the glia, dopaminergic and 'trace aminergic' modulation in the brain declines in senescence. The significant increase of the incidence of depression in the elderly, the age-dependent decline in male sexual vigor and the frequent appearance of parkinsonian symptoms in the latter decades of life might be attributed to a decrease of dopamine and 'trace amines' in the brain. The outlines of a drug strategy to counteract these biochemical lesions of aging by chronic administration of (-)deprenyl (Jumex, Eldepryl), a selective inhibitor of B-type MAO, which facilitates dopaminergic and 'trace-aminergic' activity in the brain, are forwarded. The restitution and long-term maintenance of full scale sexual activity in aged male rats continuously treated with (-)deprenyl and the clinical observation that this drug prolongs in a statistically significant manner, the duration of the Parkinson's disease support the view that (-)deprenyl may improve deteriorating functions due to dopamine deficiency in the aging brain.
 ...
PMID:The facilitation of dopaminergic activity in the aged brain by (-)deprenyl. A proposal for a strategy to improve the quality of life in senescence. 392 74

The selective monoamine oxidase (MAO) inhibitors clorgyline, selegiline and AGN 1135 did not cause a change in responses of the cat nictitating membrane to preganglionic sympathetic nerve stimulation at 5 Hz. Both selective MAO-A and MAO-B inhibitors markedly potentiated nictitating membrane contractions in response to beta-phenylethylamine (PEA). However, the responses to tyramine were unchanged. The pressor responses to tyramine were potentiated by the selective MAO-A inhibitor clorgyline (2 mg kg-1) but not by selegiline (1.0 mg kg-1) and AGN 1135 (1.5 mg kg-1), selective MAO-B inhibitors. At the doses used selegiline and AGN 1135 caused a near total selective inhibition of liver and brain MAO-B, while clorgyline inhibited MAO-A only in the brain. AGN 1135, like selegiline, could be a useful drug in potentiating the action of L-DOPA in Parkinson's disease.
 ...
PMID:Modification of blood pressure and nictitating membrane response to sympathetic amines by selective monoamine oxidase inhibitors, types A and B, in the cat. 392 10

The plasma amine oxidase (benzylamine oxidase, BzAO) of patients with Parkinson's disease is sometimes decreased in activity, when compared to normal controls. This is the result of therapy with DOPA decarboxylase inhibitors. The Authors suggest that complications due to prolonged therapy with these drugs may be, at least in part, the result of an interference with BzAO capacity to catabolize circulating amines.
 ...
PMID:Inhibitory effect of drugs used in the treatment of Parkinson's disease on plasma monoamine oxidase activity. 398 25


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