Neuroprotective actions of selegiline.
Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B.
Ebadi
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Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA. mebadi@medicine.nodak.edu
Sharma
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Shavali
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El Refaey
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D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy; D012642:Selegiline / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000978:Antiparkinson Agents; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012642:Selegiline; D007980:Levodopa