Reactive oxygen species and p38 phosphorylation regulate the protective effect of Delta9-tetrahydrocannabinol in the apoptotic response to NMDA.
NMDA causes oxidative stress in neurons, and produces cell death involving elements of both necrosis and apoptosis. To examine the neuroprotective mechanism of Delta9-tetrahydrocannabinol (THC) in NMDA-induced death of AF5 cells, we measured reactive oxygen species (ROS) formation after exposure to NMDA. ROS generation was increased by NMDA, and NMDA-induced ROS generation was significantly decreased by THC. Western blotting revealed an increase in phosphorylated p38 MAPK after NMDA treatment, which was also blocked by pretreatment with THC. The time course of ROS generation and activation of MAPK signaling pathways were similar. SB203580, a p38 inhibitor, partially blocked glutamate excitotoxicity in AF5 cells. The present data suggest that THC protects against NMDA-induced apoptosis in AF5 cells by blocking ROS generation and inhibiting the activation of p38-MAPK.
Chen
Jia
J
Development and Plasticity Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. jchen@intra.nida.nih.gov
Errico
Stacie L
SL
Freed
William J
WJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D016202:N-Methylaspartate; D013759:Dronabinol; D048051:p38 Mitogen-Activated Protein Kinases