Involvement of PGE2 and PGDH but not COX-2 in thrombin-induced cortical neuron apoptosis.
The pathways that contribute to thrombin-induced neuron death have been incompletely defined. Induction of cyclooxygenase 2 (COX-2), the enzyme that catalyzes the first step in prostaglandin synthesis, promotes neuronal injury. PGE2, a downstream product of COX-2 metabolism, is neurotoxic in vitro and in vivo, and is thought to be the bioactive mediator responsible for COX-2 neurotoxicity. The objective of this study is to determine the ability of thrombin to affect PGE2 metabolism in cultured neurons. The data show that in thrombin-induced apoptosis of cultured neurons, PGE2 release increases when COX-2 is absent, and is regulated by prostaglandin dehydrogenase (PGDH), a key enzyme that degrades PGE2. NS398, a COX-2 specific inhibitor, protects neurons against thrombin toxicity, by inducing active PGDH. These data implicate PGDH in thrombin-mediated neuronal cell death.
Thirumangalakudi
Lakshmi
L
Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS9424, Lubbock, TX 79430, United States.
Rao
Haripriya Vittal
HV
Grammas
Paula
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D006911:Hydroxyprostaglandin Dehydrogenases / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism* / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D006911:Hydroxyprostaglandin Dehydrogenases; D051546:Cyclooxygenase 2; D013917:Thrombin; D015232:Dinoprostone