Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region.
Injection of kainic acid (KA) into the brain causes severe seizures with hippocampal neuron loss. KA has been shown to immediately induce cyclooxygenase-2 (COX-2) expression in hippocampal neurons, indicating that neuronal COX-2 might be involved in neuronal death. In this study, however, we reveal that the delayed COX-2 induction in non-neuronal cells after KA injection plays an important role in hippocampal neuron loss rather than early COX-2 expression in neurons. We find that KA microinjection into the hemilateral hippocampus shows a later induction of COX-2 expression in non-neuronal cells, such as endothelial cells and astrocytes. In the KA-injected side, PGE2 concentration gradually increases and peaks at 24 h after injection, when non-neuronal COX-2 expression also peaks. When this delayed PGE2 elevation is prevented by selective COX-2 inhibitor NS398, it can block hippocampal cell death. Moreover, COX-2 knockout mice are also resistant to neuronal death after KA treatment. These findings indicate that delayed PGE2 production by non-neuronal COX-2 may facilitate neuronal death after seizure. Inhibition of COX-2 to an extent similar to PGE2 elevation after onset of seizure may be useful to prevent neuronal death.
Takemiya
Takako
T
Department of Neuropharmacology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan. takakot@tmin.ac.jp
Maehara
Michiyo
M
Matsumura
Kiyoshi
K
Yasuda
Shin
S
Sugiura
Hiroko
H
Yamagata
Kanato
K
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004790:Enzyme Induction; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009578:Nitrobenzenes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D018690:Excitatory Amino Acid Agonists; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007608:Kainic Acid