Roles of prostaglandin synthesis in excitotoxic brain diseases.
Cyclooxygenase (COX) is a rate-limiting enzyme in prostaglandin synthesis. COX consists of two isoforms, constitutive COX-1 and inducible COX-2. We have first found that COX-2 expression in the brain is tightly regulated by neuronal activity under physiological conditions, and electroconvulsive seizure robustly induces COX-2 mRNA in the brain. Our recent in-depth studies reveal COX-2 expression is divided into two phases, early in neurons and late in non-neuronal cells, such as endothelial cells or astrocytes. In this review, we present that early synthesized COX-2 facilitates the recurrence of hippocampal seizures in rapid kindling model, and late induced COX-2 stimulates hippocampal neuron loss after kainic acid treatment. Hence, we consider the potential role of COX-2 inhibitors as a new therapeutic drug for a neuronal loss after seizure or focal cerebral ischemia. The short-term and sub-acute medication of selective COX-2 inhibitors that suppresses an elevation of prostaglandin E(2) (PGE(2)) may be an effective treatment to prevent neuronal loss after onset of neuronal excitatory diseases. This review also discusses a novel role of vascular endothelial cells in brain diseases. We found that these cells produce PGE(2) by synthesizing COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in response to excitotoxicity and neuroinflammation. We also show a possible mechanisms of neuronal damage associated with seizure via astrocytes and endothelial cells. Further analysis of the interaction among neurons, astrocytes and endothelial cells may provide a better understanding of the processes of neuropathological disorders, as well as facilitating the development of new treatments.
Takemiya
Takako
T
Department of Neuropharmacology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan. takakot@lab.twmu.ac.jp
Matsumura
Kiyoshi
K
Yamagata
Kanato
K
D000818:Animals; D001927:Brain Diseases / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology; D004660:Encephalitis / Q000378:metabolism* / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis*
D009498:Neurotoxins; D011453:Prostaglandins; D011451:Prostaglandin-Endoperoxide Synthases