Nitric oxide as an upstream signal of p38 mediates hypoxia/reoxygenation-induced neuronal death.
Nitric oxide (NO) and p38 have been shown to be involved in the ischemia/hypoxia-induced neuronal injury. In this study, we examined the activation patterns of mitogen-activated protein kinases and explored the relationship between NO and p38 in a model of hippocampal neuronal death induced by hypoxia/reoxygenation (H/R). p38 activity increased robustly during hypoxia and after reoxygenation, while the increase of c-Jun amino-terminal kinase and extracellular signal-related kinase activities showed mild tendency. Inhibition of p38 with SB203580 or SB202190 rescued neuronal death, whereas inhibition of extracellular signal-related kinases with PD98059 or c-Jun amino-terminal kinases with SP600125 offered no protection. p38 inhibitors also reduced neuronal death induced by the NO donor S-nitrosoglutathione. L-NAME, a nonspecific NO synthase inhibitor, blocked the p38 activation and rescued H/R-induced neuronal death. These results suggest that NO is an upstream signal of p38 that mediates the H/R-induced neuronal death.
Chen
Ming
M
Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou, China.
Sun
Hong-Yu
HY
Li
Shu-Ji
SJ
Das
Manas
M
Kong
Ji-Ming
JM
Gao
Tian-Ming
TM
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases