Anti-ischemic effect of the novel anti-ischemic agent 2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride and possible mechanism of its action.
The protective effect of E-2001 (2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride) was examined in various ischemic models, and the mechanisms of its action were investigated in vitro and in vivo. 1. Pretreatment with E-2001 ameliorated the degeneration of pyramidal neurons in the hippocampal CA1 sector following transient ischemia in Mongolian gerbils. 2. E-2001 improved stroke symptoms induced by permanent unilateral carotid artery ligation in gerbils. 3. E-2001 prolonged the survival time following permanent bilateral carotid artery ligation in gerbils and mice. E-2001 also prolonged the survival time following intravenous injection of KCN into mice. 4. E-2001 suppressed the high potassium-evoked release of glutamate from rat hippocampal slices. Furthermore, E-2001 prevented the excessive accumulation of extracellular glutamate induced by a brief ischemia in gerbils. 5. E-2001 exerted calcium antagonistic action, i.e., a relaxing effect on high potassium-induced contraction of rat aorta. 6. E-2001 exerted inhibitory action on the lipoperoxide production in vitro and in vivo, and exhibited a radical scavenging effect against O- and N-radicals. These results suggest that E-2001 might be effective as a novel anti-ischemic agent.
Kaneko
T
T
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Nakazawa
T
T
Ueno
M
M
Furuya
Y
Y
Ikeda
M
M
Mihara
M
M
Abe
K
K
Tanaka
K
K
Uzuo
T
T
Fukuda
T
T
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005609:Free Radicals; D005849:Gerbillinae; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D011188:Potassium / Q000494:pharmacology; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats
D002317:Cardiovascular Agents; D005609:Free Radicals; D005971:Glutamates; D008054:Lipid Peroxides; D009281:Naphthalenes; D010880:Piperidines; C060312:2-(4-(4-fluorobenzoyl)piperidin-1-yl)-2'-acetonaphthone; D011190:Potassium Cyanide; D011188:Potassium