Effect of KBT-3022, a new cyclooxygenase inhibitor, on experimental brain edema in vitro and in vivo.
The effect of KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate), a new cyclooxygenase inhibitor, on experimental brain edema was studied. In vitro, KBT-3022 (100 microM) and its metabolite desethyl KBT-3022 (10 and 100 microM), but neither acetylsalicylic acid nor indomethacin, inhibited arachidonic acid-induced swelling of guinea pig cortical slices. KBT-3022 (3-100 microM) and desethyl KBT-3022 (3-30 microM), but neither acetylsalicylic acid nor indomethacin, inhibited lipid peroxidation in guinea pig brain homogenate. In vivo, oral administration of KBT-3022 (1, 3 and 10 mg/kg) and indomethacin (10 and 30 mg/kg), but not acetylsalicylic acid, prevented brain edema induced by bilateral carotid occlusion and recirculation in gerbils. Indomethacin then prevented postischemic hyperthermia, but not KBT-3022. KBT-3022 (10 mg/kg) and indomethacin (30 mg/kg) inhibited lactate accumulation in gerbil brain after ischemia and recirculation. These results suggest that KBT-3022 prevents development of both cytotoxic edema in vitro and vasogenic edema in vivo.
Yamamoto
N
N
New Drug Research Laboratories, Kanebo Ltd., Osaka, Japan.
Yokota
K
K
Yamashita
A
A
Oda
M
M
D000818:Animals; D016718:Arachidonic Acid / Q000633:toxicity; D001241:Aspirin / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005849:Gerbillinae; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D015227:Lipid Peroxidation; D008297:Male; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
D016861:Cyclooxygenase Inhibitors; D011758:Pyrroles; D013844:Thiazoles; C064847:KB 3022; D016718:Arachidonic Acid; D001241:Aspirin; D007213:Indomethacin