Neuropharmacologic aspects of apoptosis: Significance for neurodegenerative diseases

The cause of neuronal death in Parkinson's, Alzheimer's, and other neurodeg enerative diseases is not known, except in some hereditary forms of these d isorders in which a mutated gene has been identified. Even in these cases, the molecular mechanisms that underlie the loss of specific populations of neurons have not been determined, although it is highly probable that apopt osis is involved. Some of the biochemical events that occur during apoptosi s have been elucidated. We focus in this review on the role played by the p roapoptotic caspases, the antiapoptotic proteins of the Bcl-2 family, and t he apoptosis associated signal transducers such as ceramide, calcium, and r eactive nitrogen or oxygen species. The role of the mitochondria and the po ssible implication of cell cycle regulators will also be addressed. Of part icular interest are the endogenous inhibitory mechanisms and the pharmacolo gic agents that can be used to block apoptosis signaling cascades, because they offer models for the development of therapeutic strategies designed to prevent the evolution of pathologic neurodegeneration.