Nitric oxide and poly(ADP-ribose) polymerase in neuronal cell death

Mechanisms of neural damage have been of considerable clinical concern long before the augmented interest in programmed cell death, apoptosis, as a sequence of defined steps that can be approached through selective modulation of individual genes. Much of this interest involved efforts to deal therapeutically with stroke and neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. As most strokes are caused by occlusion of cerebral blood vessels, it was thought for many years that neural damage simply involved infarction of tissue due to absence of blood flow so that no therapeutic intervention would be feasible. In the case of neurodegenerative diseases, whose specific causes remain largely unknown, there was little to be done about the inexorable process of cell death. This line of thinking began to change with evidence that, following stroke, only a limited amount of tissue is infarcted due to total ischemia, while the major neural damage proceeds gradually over a day or two following toxic insult to tissue that was only partially hypoxic. Numerous toxic chemicals are released as a result of ischemia, including products of lipid peroxidation and assorted oxygen free radicals. A particularly large augmentation of glutamate release into the extracellular space occurs following vascular occlusion with 50-fold or greater increases detected by microdialysis.