Prostaglandin E2 protects cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity.
The effects of prostaglandin (PG) E2 on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to either glutamate or N-methyl-D-aspartate (NMDA) then incubated with normal medium for 1 h. Similar cytotoxicity was observed with the brief application of ionomycin, a calcium ionophore, and S-nitrosocysteine, a nitric oxide (NO)-generating agent. PGE2 at concentrations of 0.01-1 microM dose-dependently ameliorated the glutamate-induced cytotoxicity. PGE1, butaprost, an EP2 receptor agonist, and 8-bromo-cAMP were also effective in protecting cultures against glutamate cytotoxicity. By contrast, neither 17-phenyl-omega-trinor-PGE2, an EP1 receptor agonist, nor M&B 28767, an EP3 receptor agonist, affected glutamate-induced cytotoxicity. NMDA-induced cytotoxicity was ameliorated by PGE2, butaprost, MK-801, N-omega-nitro-L-arginine, a NO synthase inhibitor, and hemoglobin, which binds NO. These agents excluding MK-801 ameliorated the ionomycin-induced cytotoxicity. The cytotoxicity induced by S-nitrosocysteine was prevented only by hemoglobin but not by the other agents including PGE2. These findings indicate that PGE2 protects cultured cortical neurons against NMDA receptor-mediated glutamate neurotoxicity via EP2 receptors. EP2 receptor stimulation may suppress a step in NO formation triggered by Ca(2+)-influx through NMDA receptors.
Akaike
A
A
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Kaneko
S
S
Tamura
Y
Y
Nakata
N
N
Shiomi
H
H
Ushikubi
F
F
Narumiya
S
S
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D015232:Dinoprostone / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D015232:Dinoprostone; D002118:Calcium