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)

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.
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PMID:A review of the pharmacology of selegiline. 168 54

For patients with newly-diagnosed Parkinson's disease, current research is pointing to new therapeutic approaches. Those that are now available allow the institution of levodopa to be delayed until there is some functional disability requiring treatment. Treating mild symptoms with anticholinergics and other agents may delay the use of levodopa for up to 3 years. And when finally required, levodopa may be used at lower doses when combined with carbidopa and a dopamine agonist. The monoamine oxidase type B inhibitor selegiline is also being used by many physicians to delay the onset of disability.
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PMID:Newly-diagnosed Parkinson's disease: a therapeutic update. 172 44

It is of historical interest that 63 years ago Louis Lewin reported the use of a hallucinogenic compound prepared from the South American vine, Banisteria Caapi, to treat Parkinson's disease (PD). This psychoactive compound, named banisterine, proved to be identical to harmine, but 30 years were to pass before it was shown to be a reversible monoamine oxidase (MAO) inhibitor. The first reports of the use of banisterine to treat postencephalitic parkinsonism in 1929 created a stir in the popular press and banisterine was hailed as a "magic drug." Despite continued studies of the harmala alkaloids by other researchers, interest in the therapeutic value of these compounds vanished during the 1930's. The story of banisterine is reviewed because it was the first MAO inhibitor to be used in parkinsonism, and illustrates the historical role of psychoactive drugs in the development of effective therapies, and in elucidating the pathophysiology of PD.
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PMID:Banisterine and Parkinson's disease. 174 48

Selegiline (deprenyl) is a selective inhibitor of cerebral monoamine oxidase type B at the dosage (10 mg/day) used in patients with Parkinson's disease. Through this activity, the drug increases nigrostriatal dopamine levels, and may protect neurons against damage by free radicals and possibly exogenous neurotoxins. Selegiline also inhibits dopamine reuptake from the synaptic cleft. Because of its selectivity, selegiline 10mg daily does not prevent the breakdown and exacerbate the indirect pressor effects of dietary amines such as tyramine; it is devoid of the 'cheese' effect. Following oral administration, selegiline is rapidly metabolised to L-methamphetamine and L-amphetamine, which may account for the euphoria and insomnia seen in many patients, although potentiation of dopaminergic activity with concurrent levodopa appears more likely. The drug is a useful adjunct to levodopa in Parkinsonism, improving 'end-of-dose' fluctuations, producing modest improvements in motor function, and allowing a reduction in levodopa dosage. Indeed, if levodopa dosages are not decreased when selegiline is added to the therapeutic regimen, peak concentration dyskinesias due to levodopa are often exacerbated. However, symptomatic benefits are rarely maintained for more than a year and selegiline is relatively ineffective in allaying the abrupt swings in response to levodopa ('on/off' effects). When used alone in patients with mild disease, selegiline appears to slow the rate of symptom progression and may extend survival, through either neuroprotection or symptom relief. Whichever mechanism(s) is responsible, there is strong evidence to suggest that selegiline should be considered both in patients newly diagnosed with Parkinson's disease in an attempt to delay symptom progression, and in those experiencing dose-dependent fluctuations in response to levodopa.
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PMID:Selegiline. A review of its pharmacology, symptomatic benefits and protective potential in Parkinson's disease. 179 16

Enzymic systems involved with metabolism of foreign chemicals, xenobiotics, have been studied in Parkinson's disease. Enzymes involved with sulphur oxidation and methylation are under-active. Cysteine levels are high and sulphate levels low. Differences in the activity of the enzyme monoamine oxidase-B are evident. Pathways involved with N-methylation of pyridines are different from controls leading to a rise in potentially toxic N-methylated derivatives.
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PMID:Metabolic biomarkers of Parkinson's disease. 180 32

Four aspects about monoamine oxidase (MAO; E.C. 1.4.3.4) are of obvious interest in relation to Parkinson's disease and its treatment with the irreversible and selective MAO-B inhibitor L-deprenyl and are discussed in this review: 1) To what extent the two forms of MAO are of importance for the deamination of dopamine and to what degree MAO localised inside and outside of dopaminergic nerve terminals contributes 2) The kinetics of the MAO-protein, i.e. the rate of recovery of MAO after irreversible inhibition. 3) To what extent MAO may be changed as a consequence of the pathophysiological processes. 4) To what extent MAO may be involved as a force in the pathophysiological processes.
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PMID:Monoamine oxidase, dopamine and Parkinson's disease. 180 38

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) gives rise to motor deficits in humans and other primates which closely resemble those seen in patients with Parkinson's disease. These deficits are associated with a relatively selective loss of cells in the pars compacta of the substantia nigra and severe reductions in the concentrations of dopamine, noradrenaline and serotonin in the striatum. Similarly, in mice of various different strains the administration of MPTP also induces a marked loss of dopaminergic cells with severe depletion of biogenic amines, but higher doses of MPTP are required to produce these effects in mice than in primates. This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP. Major steps in the expression of neurotoxicity involve the conversion of MPTP to the toxic agent 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase (MAO-B) in the glia, specific uptake of MPP+ into the nigro-striatal dopaminergic neurones, the intraneuronal accumulation of MPP+, and the neurotoxic action of MPP+. This is exerted mainly through the inhibition of the enzymes of the respiratory chain (Complex I), the disturbance of Ca2+ homeostasis, and possibly by the formation of free radicals. The relevance of the MPTP model to idiopathic Parkinson's disease is discussed.
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PMID:MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. 181 82

The near IR emission at 1270 nm following pulsed laser excitation of methylene blue in deuterium oxide, was used to study the interaction of a singlet molecular oxygen (1O2) with (i) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidation products, and (ii) biosubstrates of relevance in Parkinson's disease. Steady state irradiation of methylene blue and MPTP led to a product with an absorption profile consistent with that of 1-methyl-4-phenyl-2,3-dihydropyridinium ion. This may suggest that even if monoamine oxidase enzyme activity is inhibited by the use of drugs such as Deprenyl and Paragyline the underlying conversion of MPTP to its neurotoxic oxidation product via 1O2 may still take place.
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PMID:Chemically induced Parkinson's disease. III: A study of a possible role of singlet molecular oxygen in Parkinson's disease. 181 61

This study aimed to find a possible biochemical basis for the frequent epidemiological observation of a negative correlation between smoking and Parkinson's disease. The effects of cigarette smoke exposure and of beta-naphthoflavone (BNF)-pretreatment on corpus striatal dopamine depletion by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied using the mouse MPTP model. Brain and hepatic monoamine oxidase (MAO) activity, hepatic cytochrome P450 content, BNF-inducible ethoxyresorufin O-dealkylase (EROD) activity and corpus striatal dopamine levels were measured. Cigarette smoke exposure partially protected against corpus striatial dopamine depletion by MPTP. This protection was associated with monomaine oxidase (MAO) inhibition in brain and liver, as well as with cytochrome P450 induction. BNF pretreatment also partially protected against MPTP-induced depletion of striatal dopamine. This was associated with a strong induction of cytochrome P450 but not inhibition of MAO activity. Our findings suggest that both MAO inhibition and cytochrome P450 induction may play a role in any biochemical protection afforded by cigarette smoke exposure against the development of Parkinson's disease.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: partial protection against striato-nigral dopamine depletion in C57BL/6J mice by cigarette smoke exposure and by beta-naphthoflavone-pretreatment. 188 37

Parkinson's disease (PD) is a progressive neurologic motor disorder. Currently, levodopa/carbidopa is the standard mode of therapy for PD; however, it does not prevent progression of the disease. Selegiline (also known as deprenyl), is a selective irreversible monoamine oxidase type B inhibitor virtually devoid of the tyramine reaction at the recommended dosage of 10 mg/d. It is approved by the Food and Drug Administration for the adjunctive use in the management of patients with PD who are receiving levodopa/carbidopa and exhibit a "wearing off" effect of levodopa. Numerous clinical trials have been conducted evaluating selegiline's role in the treatment of PD. Preliminary evidence from the DATATOP trial suggests that selegiline may slow the progression of PD when used as initial therapy. However, final results of this trial and additional long-term controlled trials comparing selegiline to levodopa and placebo groups are necessary to further clarify selegiline's role in the treatment of PD.
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PMID:Selegiline: initial or adjunctive therapy of Parkinson's disease? 190 Nov 85


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