Activation-induced cell death of rat astrocytes

Inflammatory activation of astrocytes has been implicated in various neurod egenerative diseases. The elimination of activated astrocytes by apoptosis or the deactivation may be the mechanisms for auto-regulation of activated astrocytes. To test the possibility of apoptotic elimination of activated a strocytes, we examined a potential correlation between activation state of astrocytes and their viability using C6 rat glial cells and rat primary ast rocyte cultures exposed to a variety of inflammatory stimuli such as lipopo lysaccharide, interferon-gamma, and tumor necrosis factor-alpha. Nitric oxi de production was measured to evaluate inflammatory activation of astrocyte s. We found that: (1) the activation of astrocytes by the combination of li popolysaccharide and inflammatory cytokines, but not by either alone, led t o nitric oxide production followed by apoptotic cell death: (ii) the amount of nitric oxide produced by activated astrocytes was inversely proportiona l to the viability of the cells; (iii) inhibition of nitric oxide synthase by N-monomethyl L-arginine blocked death of activated astrocytes; and (iv) nitric oxide donors induced apoptosis of astrocytes in a caspase-dependent manner. Taken collectively, our results suggest that activated astrocytes p roduce nitric oxide as an autocrine mediator of caspase-dependent apoptosis , and this type of programmed cell death of astrocytes may be the underlyin g mechanism for the auto-regulation of inflammatory activation of astrocyte s. (C) 2001 Elsevier Science B.V. All rights reserved.