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)

It is postulated that endogenous oxidative mechanisms are a major factor in the continuing death of dopaminergic neurons and the progression of Parkinson's disease. Scientific evidence in support of, and negating, the free radical auto-toxicity and dopamine toxicity concepts is reviewed. There is conflicting evidence whether free radicals are involved in the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and attempts to prevent the toxicity of MPTP with antioxidant therapy have had variable results. The oxidation of dopamine by monoamine oxidase produces toxic metabolites however animal studies with high dose longterm levodopa and MPTP have failed to show clear evidence for autoxidation. Firm supportive evidence is obtained from the monoamine oxidase B inhibitor experience which demonstrated a block of the toxicity of MPTP in animals and probable prolongation of the course of human Parkinson's disease. The scientific data available is inconclusive but there is significant hope of retarding progressive catecholaminergic neuron degenerative changes by augmenting the free radical scavenging system with antioxidants (such as Vitamin E) and slowing catecholamine oxidation by monoamine oxidase B inhibition. Careful clinical trials with these agents must be performed.
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PMID:Antioxidant therapy in Parkinson's disease. 331 49

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes selective destruction of dopaminergic neurons of the nigrostriatal pathway in humans and other primates. It is less specific and much less potent in mice and has only slight effects in rats. Differences in rates and sites of metabolism of MPTP to its active, toxic, highly polar metabolite, MPP+ (1-methyl-4-phenylpyridine), appear to influence species specificity. In rats, type B monoamine oxidase (MAO-B), which mediates the conversion of MPTP to MPP+, may act as an enzymatic barrier at brain microvessels, whereas in primates the enzyme, present mainly in astrocytes, appears important for bioactivation of MPTP into the toxic metabolite. MPP+ is a substrate for catecholamine uptake sites and is concentrated in these neurons. The molecular mechanism of MPP+ toxicity has not been established definitively, but conversion to a free radical or uptake by mitochondria and inhibition of mitochondrial respiratory enzymes, leading to calcium release and cell death have been suggested. The discovery of toxin which causes an animal model of Parkinson's disease has stimulated new research on environmental factors that might contribute to this progressive degenerative disorder and provides a means for assessing new approaches to therapy.
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PMID:MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson's disease. 331 63

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.
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PMID:Monoamine oxidase B, smoking, and Parkinson's disease. 348 45

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.
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PMID:The significance of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 355 86

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.
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PMID:Central and peripheral catecholamine depletion by 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in rodents. 387 Dec 44

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.
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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

Monoamine oxidase (MAO) is distributed in neurons and non-neuronal tissue in the human central nervous system. It occurs there as MAO type A and MAO type B. It is not, however, established where both types are located intra- and/or extra-neuronally. Recently, the use of selective MAO-B blockers has shown beneficial effects in the treatment of Parkinson's disease (PD). Knowledge about the locus of action of MAO inhibitors is therefore of great importance. Our findings indicate that MAO-B inhibitors like deprenyl act by blocking neuronal and extra-neuronal MAO-B. This demonstrates that in the early stages of PD the action of deprenyl improves dopamine neurotransmission and hormonal action, whereas in the advanced stages of the disease, when there is progressive loss of dopaminergic neurons accompanied by gliosis, the drug seems to exert beneficial effects via the hormonal route.
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PMID:Neurochemical insights into monoamine oxidase inhibitors, with special reference to deprenyl (selegiline). 614 82

The role of deprenyl, a selective monoamine oxidase B inhibitor, in the treatment of Parkinson's disease has been evaluated with special reference to the multiple pharmacological actions of the monoamine oxidase-inhibitory group of drugs.
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PMID:Monoamine oxidase inhibitors and their pharmacological significance. 642 47

Deprenyl inhibits MAO-B selectively in different animal species and in man. Its safety margin is remarkable. We were able to block MAO-B activity in the brain selectively in vivo in four species (mouse, rat, cat, dog) with s.c. administration of 0.17-0.31% of LD50. The usual oral dose range in clinical practice, 5-20 mg daily (0.05-0.2 mg/kg), is about ten times lower than the orally active dose in the rat. Deprenyl proved to be safe drug in man. Neither hypertensive reactions nor the need for any special dietary care were ever encountered during long-term (2-8 years) daily administration of the drug. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences, but in contrast to levodopa or bromocrytine, deprenyl does not elicit an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine. In agreement with its peculiar spectrum of pharmacological activity, deprenyl proved to be a useful adjuvant to levodopa alone or in combination with a peripheral decarboxylase inhibitor. In addition, a supplement of deprenyl in Parkinson's disease led to significant prolongation of the duration of the illness. This has not been observed so far with other antiparkinsonian drugs. The dopamine content of the human caudate nucleus decreases by 13% per decade over the age of 45. The hypothesis has been put forward that the significant increase of incidence of depression in the elderly, the age-dependent decline in male sexual vigour and the frequent appearance of parkinsonian symptoms in the later decades of life might be attributed to a decrease of dopamine and 'trace amines' in the brain. The possibility of countering these biochemical lesions of ageing by long-term administration of deprenyl, a selective inhibitor of MAO-B which facilitates dopaminergic and 'trace-aminergic' activity in the brain, and is a safe drug in man, is considered in detail.
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PMID:Deprenyl (selegiline): the history of its development and pharmacological action. 642 48

Significant reduction in brain weight and in the number of cortical neurons with increase of astroglia in aging brain and SDAT are associated with decreased synthesis and turnover of some neurotransmitters, particularly affecting the DAergic system. Progressive loss of TH activity reaching in SDAT almost the low levels of Parkinson disease is associated with progressive decline in DA concentration in the nigro-striatal system. Increase in MAO-B activity and in the ratio of MAO-B: MAO-A reported by some authors in aging brain and SDAT, however, was not confirmed in human frontal cortex in both Parkinson disease and SDAT. However, the location of both types of MAO in human brain is debatable, since preliminary studies indicate that, unlike in rat brain, MAO-B appears to be the major degradating enzyme of biogenic amines in human brain, while MAO-A might be associated, at least in part, with neuronal structures. Reduction in DAergic parameters in aging brain are also reflected in a decrease of adenylate cyclase activity and of D2 DA receptors. Animal data on decrease of DA-receptor density in the striatum with age were confirmed in human Parkinson disease and Alzheimer disease. These disturbances in neuronal feedback systems may be responsible for pathophysiological and behavioral changes in old age.
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PMID:Morphological and biochemical changes in the aging brain: pathophysiological and possible therapeutic consequences. 715 7


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