ROLE OF APOPTOSIS IN ACUTE NEURODEGENERATIVE DISORDERS

Many toxic factors are generated during stroke that contribute directl y to the death of neurons. Several recent studies suggest that a suici de-like phenomena similar to apoptosis or programmed cell death also c ontributes to the loss of neurons in stroke. The evidence implicating apoptosis in stroke can be divided into three categories; biochemical, molecular and pharmacological. Biochemical evidence: One hallmark of apoptosis is the early activation of destructive enzymes, including en donucleases and proteases. Endonuclease-mediated DNA fragmentation can be observed within 4 h after focal cerebral ischemia and precedes mor phological evidence of cell death. Cells with damaged DNA appear to co ncentrate in the salvageable tissue of the penumbra while necrosis pre dominates in areas where the sustained lack of blood flow may make tis sue salvage impossible. Molecular evidence: Bcl-2 is an anti-apoptotic gene that confers the ability to block apoptosis from a wide variety of stimuli. The levels of bcl-2 can be enhanced by viral gene delivery or transgenic methodology. In cortical tissue where bcl-2 was elevate d, neurons were protected from a subsequent ischemic attack. In contra st to bcl-2, p53 is a pro-apoptotic protein. Levels of p53 are elevate d after cerebral ischemia and transgenic p53 knockouts exhibit smaller infarcts than wild type control mice. Pharmacological evidence: The p rocess of apoptosis typically involves the activation of enzymes and g enes, leading to an irreversible committment to die. Inhibition of new protein synthesis by cycloheximide reduces brain damage after a strok e, suggesting that newly synthesized proteins are contributing to the death of neurons. In addition, inhibition of calpain (an enzyme implic ated in certain forms of apoptosis) protects neurons in models of glob al ischemia, focal ischemia, and hypoxia. In conclusion, the observati on that an apoptotic-like process contributes to stroke may have impor tant therapeutic implications since therapies that inhibit apoptosis i mprove outcome in experimental stroke.