Reduction of neuronal apoptosis by small molecules: Promise for new approaches to neurological therapy

Publisher Summary Several members of the neurotrophin, mitogen, and cytokine/neurokine families have the capacity to reduce or slow neuronal apoptosis. Each of these neurotrophic factors act on specific receptors, which activate a number of cellular processes, some of which lead to a reduction in neuronal death. Deprenyl was synthesized as a psychoenergizer that combined (−)-metham–phetamine with a pargene chain and was subsequently found to selectively inhibit the B form of monoamine oxidase (MAO-B). Levodopa and (−)-deprenyl were used in combination to treat Parkinson's disease in the hope that levodopa would be converted to dopamine by nigrostriatal neurones, and (−)-deprenyl would cause an acute decrease in dopamine metabolism, thereby increasing dopamine availability in the striatum. The celebrated finding that MAO-B inhibition protected nigrostriatal neurones from damage caused by the toxin MPTP, presumably by blocking the conversion of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenylpyridinum (MPP + ) in astroglia, reinforced the view that (−)-deprenyl could have clinical utility as an MAO-B inhibition-dependent neuroprotectant. The results indicate that three of the four MAO-independent actions of (−)-deprenyl result from selective alterations in gene expression induced by (−)-desmethyldeprenyl.