Apoptotic and antiapoptotic mechanisms in stroke

Apoptosis is a form of programmed cell death that occurs in neurons during development of the nervous system and may also be a prominent form of neuro nal death in chronic neurodegenerative disorders such as Alzheimer's and Pa rkinson's diseases. Recent findings also implicate apoptosis in neuronal de generation after ischemic brain injury in animal models of stroke. Activati on of both apoptotic and antiapoptotic signaling cascades occurs in neurons in animal and cell culture models of stroke. Apoptotic cascades involve: i ncreased levels of intracellular oxyradicals and calcium; induction of expr ession of proteins such as Par-4 (prostate apoptosis response-it), which ac t by promoting mitochondrial dysfunction and suppressing antiapoptotic mech anisms; mitochondrial membrane depolarization, calcium uptake, and release of factors (e.g., cytochrome c) that ultimately induce nuclear DNA condensa tion and fragmentation; activation of cysteine proteases of the caspase fam ily, activation of transcription factors such as AP-1 that may induce expre ssion of "killer genes." Antiapoptotic signaling pathways are activated by neurotrophic factors, certain cytokines, and increases in oxidative and met abolic stress. Such protective pathways include: activation of the transcri ption factors (e.g., nuclear factor-kappa B, NF-kappa B) that induce expres sion of stress proteins, antioxidant enzymes, and calcium-regulating protei ns; phosphorylation-mediated modulation of ion channels and membrane transp orters; cytoskeletal alterations that modulate calcium homeostasis; and mod ulation of proteins that stabilize mitochondrial function (e.g., Bcl-2). In tervention studies in experimental stroke models have identified a battery of approaches of potential benefit in reducing neuronal death in stroke pat ients, including administration of antioxidants, calcium-stabilizing agents , caspase inhibitors, and agents that activate NF-kappa B. Interestingly, r ecent studies suggest novel dietary approaches (e.g., food restriction and supplementation with antioxidants) that may reduce brain damage following s troke.