Excitotoxicity-induced prostaglandin D2production induces sustained microglial activation and delayed neuronal death.
Excitotoxicity is the pivotal mechanism of neuronal death. Prostaglandins (PGs) produced during excitotoxicity play important roles in neurodegenerative conditions. Previously, we demonstrated that initial burst productions of PGD2, PGE2, and PGF2αare produced by cyclooxygenase-2 (COX-2) in the hippocampus following a single systemic kainic acid (KA) administration. In addition, we showed that blocking of all PG productions ameliorated hippocampal delayed neuronal death at 30 days after KA administration. To investigate the role of individual PGs in the delayed neuronal death, we performed intracerebroventricular injection of PGD2, PGE2, or PGF2αin rats whose hippocampal PG productions were entirely blocked by pretreatment of NS398, a COX-2 selective inhibitor. Administration of PGD2and PGF2αhad a latent contribution to the delayed neuronal death, sustained over 30 days after a single KA treatment. Furthermore, PGD2enhanced microglial activation, which may be involved in the delayed neuronal death in the hippocampus. These findings suggest that excitotoxic delayed neuronal death is mediated through microglia activated by PGD2.
Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan.
Kensuke
K
Iwasa
Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan.
Shinji
S
Yamamoto
Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan.
Sosuke
S
Yagishita
Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan.
Kei
K
Maruyama
Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan. Electronic address: keisukey@saitama-med.ac.jp.
Keisuke
K
Yoshikawa
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007608:Kainic Acid / Q000008:administration & dosage*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009578:Nitrobenzenes / Q000008:administration & dosage; D015230:Prostaglandin D2 / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage
D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2; D007608:Kainic Acid
kainic acid; microglia; neurons