A transient brain ischemia- and bacterial endotoxin-induced glial iNOS expression and NO-induced neuronal apoptosis.

Astroglia cells seem to be closely involved in neuronal survival/death via neurotrophins, cytokines and so on. We found that a transient four-vessel occlusion/reperfusion induced glial iNOS expression and neuronal apoptosis in a CA1 region of the rat hippocampus. Bacterial endotoxin (LPS)/INFgamma induced iNOS expression in cultured C6 rat glioma cells. LPS caused intranuclear translocation of NF-kappaB, and IFNgamma induced phosphorylation of Jak2 and Stat1, followed by the translocation of Stat1 into the nucleus. A NO donor (SNP) caused chromosomal condensation and fragmentation of nuclei and internucleosomal DNA fragmentation in NG108-15 cells, suggesting NO-induced neuronal apoptosis. Koningic acid (KO), a chemical modifier and enzyme inhibitor of glyceraldehyde-3 phosphate dehydrogenase (GAPDH), induced the apoptosis too. In addition, a NO donor (NOC18)-induced apoptosis was inhibited by Z-Asp-CH2-DCB, a caspase inhibitor, in SH-SY5Y cells. NOC18 increased caspase 3-like proteolytic activity to a substrate (Ac-DEVD-MCA), indicating the involvement of caspase, at least caspase 3, in NO-induced neuronal apoptosis.