Neuroprotective actions of selegiline

Abstract

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-␤-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. © 2002 Wiley-Liss, Inc.Selegiline (deprenyl; Jumex), a noncompetitive monoamine oxidase-B (MAO-B) inhibitor, has continued to hold a fascination for clinicians and researchers since it was first synthesized as a "psychic energizer." The "neuroprotective effects" of selegiline became evident when it was found that it blocked the parkinsonism-inducing effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; see Langston and Tanner, 2000).MPTP as a neurotoxin has attracted the attention of many investigators owing to its capacity in humans and nonhuman primates to induce neuropathologic abnormalities (rigidity, resting tremor, akinesia, etc.) similar to those observed in patients with idiopathic Parkinson's disease (PD). As in PD also after administration of MPTP, the observed symptoms are caused by depletion of dopamine in the neostriatum following selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNpc).MPTP's capacity to induce PD was discovered accidentally when several drug addicts in California developed numerous symptoms of PD after self-administration of a "synthetic heroin" containing MPTP as a contaminant byproduct. Numerous investigations have since been carried out in which MPTP was administered in vivo to primates and rodents as well as in vitro using cell cultures. Today, MPTP-induced toxicity represents one of the most interesting models for investigating the pathogenesis of the parkinsonian syndrome. However, its mechanism of action is stil...

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

“…Within the dentate gyrus, immunohistochemical procedures revealed the polysialylated cells to be located specifically at the infragranular zone with a well-established dendritic arbor extending through the granule cell zone and into the overlying molecular layer (Figure 3). Nefiracetam, a well-established nöotrope (Shorvon, 2001) and the neuroprotective drug deprenyl (Ebadi et al, 2002) were employed to determine if increased dentate polysialylated cell frequency followed chronic administration of other agents that enhance acetylcholine and memory function. Nefiracetam exhibited an action very similar to that observed with tacrine.…”

The Effect of Some Organic Compounds on Monoamino oxidase Activity

“…Despite considerable progress in understanding the interactions of the two enzyme forms with their preferred substrates and inhibitors, no general rules are yet available for the rational design of potent and selective inhibitors of MAO possibly due to the fact that the mechanism of interaction of the new drugs with MAO isoforms have not been fully characterized. Preferential MAO-A inhibitors have been recognized as therapeutically useful antidepressants while MAO-B inhibitors have been found to be beneficial in the treatment of Parkinson's disease and Alzheimer [18,19,20] . Bellik L.etal [21] , reported that the novel MAO-B inhibitor PF9601N, its cytochrome P450-dependent metabolite FA72 and l-deprenyl were studied as potential peroxynitrite (ONOO) scavengers and nitric oxide synthase (NOS) inhibitors both the novel MAO-B inhibitor as well as its metabolite were able to strongly inhibit rat brain neuronal NOS (IC50 of 183 μM and 192 μM, respectively), while l-deprenyl at the highest concentration used (3 mM), caused only a slight decrease of the enzyme activity.…”

Synthesis of Deprenyl-like nitroxide free radicals and their diamagnetic derivatives

“…In order to preserve brain dopamine, it is also common to treat patients with a monoamine oxidase B (MAO-B) inhibitor. 4 Selegiline (L-Deprenyl) and Rasagiline ( Figure 1) [5][6][7][8][9][10] are selective inhibitors of MAO-B and Selegiline is currently used for the treatment of Parkinson's and Alzheimer's diseases. This compound was reported to have a neuroprotective activity due to the prevention of apoptosis.…”