The Role of Programmed Cell Death in Cerebral Ischemia

Abstract

Following transient global cerebral ischemia, there is a progressive increase in nitric oxide (NO) synthase activity in hippocampal CA1 neurons that may be enhanced by a lack of protein inhibitor of neuronal NO synthase (PIN). The concomitant accumulation of NO and other reactive oxygen species causes deoxyribonucleic acid (DNA) injury, as indicated by the futile attempt to activate the DNA repair enzyme, ref-1, and by the expression of DNA damage-inducible, cell death-promoting PAG608 in CA1 neurons 1 day after ischemia. Nuclear phospho-c-Jun(Ser-73) immunoreactivity becomes apparent in CA1 cells, suggesting that oxidative stress and DNA damage activate c-Jun N-terminal kinases. One day after ischemia, expression of caspase-3 is upregulated in CA1 neurons and caspase-3-like proteolytic activity increases in hippocampal extracts. Intracerebroventricular infusion of the caspase inhibitor, Z-DEVD-FMK, prevents CA1 cell loss, indicating that CA1 cells die by programmed cell death. Following transient focal ischemia, PIN transcripts and phospho-c-Jun rapidly accumulate in neurons of the reperfused cortex. Immunoreactivity for Bcl-2-associated death protein (Bad) becomes apparent in post-ischemic cortical neurons. Furthermore, the infarct area is significantly larger in bcl-2-deficient mice, strongly suggesting that Bcl-2 and related proteins influence neuronal cell death after focal ischemia.