INDUCTION OF PROTEIN INHIBITOR OF NEURONAL NITRIC-OXIDE SYNTHASE CYTOPLASMIC DYNEIN LIGHT-CHAIN FOLLOWING CEREBRAL-ISCHEMIA

Administration of inhibitors of neuronal nitric oxide synthase or dele tion of the encoding gene in rodents provided evidence that neuronal n itric oxide synthase activity may contribute to neuronal cell death fo llowing global and focal cerebral ischemia. In the present study, we i nvestigated by in situ hybridization the expression of an endogenous i nhibitor of neuronal nitric oxide synthase activity, designated protei n inhibitor of neuronal nitric oxide synthase and homologous to cytopl asmic dynein light chain, in the post-ischemic rat brain. Following gl obal ischemia induced by cardiac arrest, messenger RNA expression of p rotein inhibitor of neuronal nitric oxide synthase was rapidly induced in pyramidal neurons of the hippocampal CA3 region and granule cell o f the dentate gyrus which are resistant to ischemic damage. In vulnera ble CA1 pyramidal neurons however, protein inhibitor of neuronal nitri c oxide synthase expression remained at basal level after global ische mia and was associated with an increase in nicotinamide adenine dinucl eotide phosphate-diaphorase activity and subsequent DNA fragmentation indicating ischemia-mediated neuronal cell death. Following focal cere bral ischemia induced by permanent occlusion of the middle cerebral ar tery, transcripts of protein inhibitor of neuronal nitric oxide syntha se progressively accumulated in cortical neurons bordering the infarct area. After transient middle cerebral artery occlusion however, messe nger RNA levels of protein inhibitor of neuronal nitric oxide synthase increased in the reperfused neocortex. Our findings indicate that cer ebral ischemia leads to an increase in neuronal expression of protein inhibitor of neuronal nitric oxide synthase in brain regions where sus tained or ''uncoupled'' nitric oxide synthase activity may be detrimen tal to neurons. Lack of post-ischemic induction of protein inhibitor o f neuronal nitric oxide synthase in CA1 pyramidal neurons may result i n high nitric oxide synthase activity after global ischemia and could contribute to delayed neuronal cell death. (C) 1998 IBRO. Published by Elsevier Science Ltd.