Selegiline (l-Deprenyl) as a Unique Neuroprotective Agent for Chronic Neurodegenerative Disorders- A Lesson from MAO Inhibition

The purpose of this review is to describe recent advances in understanding the neuroprotective effects of selegiline (N-propanyl-l-amphetamine; l-deprenyl) and the development of a variety of novel and interesting propargyl compounds that might be potentially useful in the treatment of chronic neurodegenerative brain disorders. Selegiline is a selective, non-competitive, irreversible inhibitor of monoamine oxidase (MAO) B, and is widely used as an adjunct to Ldopa in the treatment of Parkinson's disease. Recent interest in selegiline has focused on its complex neuroprotective actions against a variety of neurotoxins, and on the pathological processes of oxidative stress and apoptosis which cause neuronal death in chronic neurodegenerative brain disorders, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. These neuroprotective effects of selegiline are due not only to MAO-B inhibition, but also to many other effects, such as suppression of free radical formation elicited by MPP+ and glutamate, up regulation of the antioxidative enzymes, superoxide dismutase and catalase, induction of proteins interfering with the apoptotic pathway, and expression of neurotrophic factors. Recent molecular biological evidence suggests that selegiline may also alter the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and other redox active molecules such as thioredoxin in brain neurons. These unique neuroprotective mechanisms of selegiline may provide models for the synthesis of new Npropargyl analogues with different structure-activity relationships, and for the development of therapeutic strategies designed to prevent the evolution of pathologic neurodegeneration.