■ REVIEW : Excitotoxicity,Free Radicals,Necrosis,and Apoptosis

Abstract

Recent studies have shown that excitotoxicity can result in either neuronal necrosis (passive cell lysis associated with energy failure) or apoptosis (active cell death requiring energy production). The type of cell death encountered by neuronal cell cultures exposed to excessive levels of excitatory amino acids—such as glutamate, the major excitatory neurotransmitter in the central nervous system, or free radicals, such as nitric oxide (NO) and superoxide anion (O₂ ^-), which react to form peroxynitrite (ONOO-)—depends on the intensity of the exposure and may involve two temporally distinct phases. After relatively fulminant insults, an initial phase of necrosis—associated with extreme energy depletion—may simply reflect the failure of neurons to carry out the "default" apoptotic death program used to efficiently dispose of aged or otherwise unwanted cells. Neurons that survive this initial insult recover mitochondrial membrane potential and energy charge and subsequently undergo apoptosis, which seems to be associated with a factor(s) released from mitochondria. These factors have proteolytic activity or trigger the activation of proteases (caspases), ex ecutors of the cell death program. Thus, the maintenance of balanced energy production may be a decisive factor in determining the degree, type, and progression of neuronal injury caused by excitotoxins and free radicals. Increasing evidence suggests that similar events occur in vivo after ischemia or other insults, including Alzheimer's disease, Huntington's disease, and AIDS dementia. NEUROSCIENTIST 4:345-352, 1998