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)

Based on mechanistic understandings, molecular modeling and extensive quantitative structure-activity relationships, appropriately substituted haloallylamine derivatives were designed as potential mechanism-based inhibitors of MAO and/or SSAO. Potent inhibition of MAO-B and SSAO occurred with fluoroallylamines whereas chloroallylamines, such as MDL 72274A ((E)-2-phenyl-3-chloroallylamine hydrochloride), were selective and potent inhibitors of SSAO. MDL 72974A (E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride is a potent (IC50 = 10(-9) M) inhibitor of both MAO-B and SSAO, with 190-fold lower affinity for MAO-A. In clinical studies, oral doses as low as 100 micrograms produced substantial inhibition of platelet MAO-B. Essentially complete inhibition occurred at 1 mg with the effect lasting 6-10 days. One or 4 mg MDL 72974A given daily for 28 days to 40 Parkinson's patients treated with L-dopa produced statistically significant reductions in the Unified Parkinson's Disease Rating Scale. MAO-B inhibitors, such as MDL 72974A and L-deprenyl, offer the potential of being neuroprotective in Parkinson's Disease and other neurogenerative disorders. Concommitant inhibition of SSAO may provide additional, but as yet unproven, advantages over pure inhibitors of MAO-B.
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PMID:Haloallylamine inhibitors of MAO and SSAO and their therapeutic potential. 793 Dec 57

Deprenyl, a selective monoamine oxidase B inhibitor, is effective in Parkinson's disease, and can slow the cognitive deterioration in Alzheimer's disease. However, it is not known whether this agent has a trophic effect on spinal motor neurons. We have studied neurotrophic effects of deprenyl on spinal motor neurons, using explanted ventral spinal cord culture from 13-day-old rat embryos. Deprenyl-treated cultures significantly enhanced neurite outgrowth with cultures of ventral spinal cord. Our data suggest that deprenyl is one of the candidate for neurotrophic factors on spinal motor neurons in vitro. A possible role for deprenyl in amyotrophic lateral sclerosis remains to be defined.
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PMID:Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons. 796 80

The acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor, l-deprenyl (l-selegiline), has proved to be a useful adjuvant to L-dopa therapy and monotherapy of Parkinson's disease. Although not all features of its antiParkinson action are known, studies that used brains obtained at autopsy from patients who took l-deprenyl show that the selective inhibition of MAO-B with a concomitant increase of phenylethylamine and dopamine, but not of serotonin or noradrenaline, in the basal ganglia may be responsible for its mode of action. The increased life expectancy noted in patients with Parkinson's disease who received long-term therapy (9 years in an uncontrolled study) is another unexpected feature of the drug. These exciting data, if confirmed in other long-term clinical trials, may herald a neuroprotective approach to the treatment of this degenerative disease. More recent studies indicate that Parkinson's disease may eventually turn out to be a neurotoxic event resulting from oxidative stress-induced free radical species in the substantia nigra. Thus selective MAO-B inhibitors could represent a unique class of drugs, having symptomatic actions with possible neuroprotective and neurorescue actions in one.
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PMID:Pharmacological actions of l-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors. 799 14

l-Deprenyl is a selective, irreversible monoamine oxidase (MAO) type B inhibitor. Dopamine is a relatively good MAO-B substrate in the human brain. Because Parkinson's disease is characterized by a decrease in dopaminergic neurotransmission in the basal ganglia, the selective inhibition of MAO-B should lead to diminished metabolism of dopamine in the nigrostriatal system and a significant increase in the concentration of the neurotransmitter. MAO-B inhibition explains the clinical efficacy of l-deprenyl in the treatment of Parkinson's disease and the prevention of the conversion of protoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is oxidized by MAO-B and can cause a parkinsonian syndrome, to their active neurotoxin. In addition, l-deprenyl appears to exhibit other biochemical actions that are independent of its MAO-B activity. These actions may be the basis of the neuroprotective effects of l-deprenyl and may include the inhibition of oxidative stress, an indirect influence on the polyamine binding site of the N-methyl-d-aspartate receptor and the stimulation of neurotrophic factors.
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PMID:Biochemical actions of l-deprenyl (selegiline). 799 15

The MAO-B inhibitor selegiline is used in the treatment of Parkinson's disease. Further, beneficial effects in Alzheimer's disease have also been described as well as neuroprotective effects, increased longevity and an attenuation of age-related cognitive decline in experiments using rats. Our studies in mice and Syrian hamsters aim at the question whether the effects of selegiline reported in the rat can be generalized to other species. Aged female NMRI-mice (23 mo.) treated with selegiline (0.25 mg/kg, i.p., 3 times a week for 2-3 weeks) showed no treatment effect in the Morris water maze and in passive avoidance learning after 2 and 3 weeks of treatment. However, Syrian hamsters chronically treated with selegiline (0.05 mg/kg/day in the food, starting at 12 months old) showed a 3 month delay in the age-related decline of spontaneous alteration behavior, a measure of longer-term memory, compared to untreated controls. Since treated hamsters also show increased longevity (study still in progress) the data suggest a protective effect of a chronic treatment with selegiline against age-related cognitive and physical decline.
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PMID:Age-related memory decline and longevity under treatment with selegiline. 799 74

To confirm the clinical utility of selegiline (L-deprenyl), a selective inhibitor of monoamine oxidase B, as an anti-Parkinson's disease (PD) agent, the first Japanese multi-center, double-blind comparative study of this drug was conducted. The subjects were patients who had responded poorly or suffered with other problems related to L-dopa treatment. A total of 112 patients in two groups, one given selegiline at a dose of 7.5 mg/day (Group D, n = 60) and another given a placebo (Group P, n = 52), were compared over an 8-week treatment period. The percentage patients showing "moderate improvement" or better was 34.5% in Group D, while that in Group P was 11.5% (P < 0.01). In the assessment of overall safety, 66.7% in Group D showed no adverse reactions, which was not significantly different from the result of 78.9% for Group P.
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PMID:Selegiline (L-deprenyl) and L-dopa treatment of Parkinson's disease: a double-blind trial. 800 Jan 1

(-)Deprenyl, a MAO-B inhibitor that is also known to be effective for symptoms of Parkinson's disease, when injected subcutaneously (sc) in male Fischer-344 rats at a dose of 0.5 mg/kg per day (3 times a week) from 18 months of age, significantly increased the remaining life expectancy. The average life span after 24 months was 34% greater in treated rats than in saline-treated control animals. Furthermore, a short-term (3 wk) continuous sc infusion of deprenyl significantly increased activities of superoxide dismutase and catalase but not of glutathione peroxidase in selective brain regions such as s. nigra, striatum, and cerebral cortex, but not in hippocampus or cerebellum, or the liver. The optimal dose for increasing these activities, however, differed greatly depending on the sex and age of animals, with a 10-fold lower value for young female than male rats. Interestingly, aging caused an increase and a decrease in the optimal dose in female and male rats, respectively. In addition, treatment for a longer term tended to reduce the optimal dosage in the same animal group. The results clearly demonstrate that deprenyl increases antioxidant enzyme activities in selective brain regions. If this effect of deprenyl is causally related to its life-prolonging effect, the dosage to be used for any life span study would be a critical factor, with the dosage differing widely depending on sex, age of animal, and mode and duration of drug administration.
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PMID:(-)Deprenyl increases the life span as well as activities of superoxide dismutase and catalase but not of glutathione peroxidase in selective brain regions in Fischer rats. 803 Aug 52

The discovery of a selective striatal dopamine deficiency in Parkinson's disease has led to dopamine replacement therapies including L-DOPA, dopamine full and partial agonists, and MAO-B inhibitors. The development of new compounds and alternative methods of drug delivery may be able to overcome the long-term side effects of the established therapies. Overactivity of central glutamatergic systems appears to be important in the pathophysiology of the disorder and provides the rationale for the use of glutamate antagonists. Recent studies emphasize the significance of oxidative stress and free radical formation in the pathogenesis of Parkinson's disease. Future research will focus on improvements in neuroprotective therapy to prevent or slow the rate of progression of the disease. Possible neuroprotective strategies include selective MAO-B inhibitors, iron chelators, and free radical scavengers.
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PMID:Recent advances in pharmacological therapy of Parkinson's disease. 809 82

Rats have been described as being insensitive to relatively high doses of systemically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that in primates induces a neurological syndrome identical to idiopathic Parkinson's disease. The current explanation for the rat resistance is that most of the MPTP is converted into the toxic metabolite 1-methyl-4-phenylpyridium (MPP+) by the MAO-B present in the brain vessel endothelium. Since MPP+ is a polar compound, a very low amount could cross the blood-brain barrier and be present inside the brain. We administered C57 BL mice and Brown Norway rats with either MPTP (30 mg/kg, ip) or the combined treatment MPTP + diethyldithiocarbamate (DDC). In mice, DDC prolonged the striatal exposure to MPP+, potentiated the MPTP-induced acute syndrome, and enhanced the MPTP-induced striatal dopamine depletion. In rats, DDC potentiated the MPTP-induced acute syndrome, but no changes in the striatal dopamine were observed after either MPTP or DDC + MPTP administration. Also in rats, however, high doses of MPP+ were measured in the striatum of MPTP-alone treated rats and DDC delayed the MPP+ elimination from the striatum. When MPTP alone or DDC + MPTP was administered to rats unilaterally lesioned with 6-hydroxy dopamine (6-OH-DA), the levels of MPP+ measured in the intact striatum were significantly higher than those found in the 6-OH-DA-lesioned striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In brown Norway rats, MPP+ is accumulated in the nigrostriatal dopaminergic terminals but it is not neurotoxic: a model of natural resistance to MPTP toxicity. 820 Apr 37

The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO-B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.
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PMID:Monoamine oxidase inhibition by L-deprenyl depends on both sex and route of administration in the rat. 827 94


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