Activation-induced cell death of rat astrocytes.
Inflammatory activation of astrocytes has been implicated in various neurodegenerative 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 astrocytes, we examined a potential correlation between activation state of astrocytes and their viability using C6 rat glial cells and rat primary astrocyte cultures exposed to a variety of inflammatory stimuli such as lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha. Nitric oxide production was measured to evaluate inflammatory activation of astrocytes. We found that: (i) the activation of astrocytes by the combination of lipopolysaccharide and inflammatory cytokines, but not by either alone, led to nitric oxide production followed by apoptotic cell death; (ii) the amount of nitric oxide produced by activated astrocytes was inversely proportional 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 produce nitric oxide as an autocrine mediator of caspase-dependent apoptosis, and this type of programmed cell death of astrocytes may be the underlying mechanism for the auto-regulation of inflammatory activation of astrocytes.
Suk
K
K
Department of Herbal Pharmacology, Graduate School of East-West Medical Science, Kyung Hee University, Hoegi-dong, Tongdaemun-ku, 130-701, Seoul, South Korea. ksuk@nms.kyunghee.ac.kr
Lee
J
J
Hur
J
J
Kim
Y S
YS
Lee
M
M
Cha
S
S
Yeou Kim
S
S
Kim
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D020169:Caspases