T-588 inhibits astrocyte apoptosis via mitogen-activated protein kinase signal pathway.
The effect of (1R)-1-benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan -1-ol hydrochloride (T-588), a cognition enhancer, on reperfusion injury was studied in cultured rat astrocytes. T-588 at 1-10 microM partially protected astrocytes against reperfusion injury after exposure to Ca(2+)-free medium or hydrogen peroxide. Nerve growth factor (NGF) had a similar protective effect. Addition of both T-588 and NGF resulted in complete protection against Ca(2+) reperfusion injury. T-588 did not stimulate NGF production in astrocytes. The effect of T-588 on Ca(2+) reperfusion injury including apoptosis was inhibited by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059), but not by the phosphoinositide 3-kinase inhibitor wortmannin. The effect of NGF was inhibited by PD98059 and wortmannin. T-588 stimulated rapidly the phosphorylation of ERK, but did not affect that of Akt in astrocytes. These findings suggest that the ERK MAP kinase pathway has a role in the protective effects of T-588 and NGF.
Takuma
K
K
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 518 Arise, Ikawadani-cho, Nishi-ku, 651-2180, Kobe, Japan.
Fujita
T
T
Kimura
Y
Y
Tanabe
M
M
Yamamuro
A
A
Lee
E
E
Mori
K
K
Koyama
Y
Y
Baba
A
A
Matsuda
T
T
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004048:Diethylamines / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control; D013876:Thiophenes / Q000494:pharmacology*; D000077191:Wortmannin
D000730:Androstadienes; D000697:Central Nervous System Stimulants; D004048:Diethylamines; D013876:Thiophenes; C082372:T 588; D020932:Nerve Growth Factor; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin