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 mu M partially protected astrocytes against reperfusion injury after exposure to Ca2+-free medium o r hydrogen peroxide, Nerve growth factor (NGF) had a similar protective eff ect. Addition of both T-588 and NGF resulted in complete protection against Ca2+ reperfusion injury. T-588 did not stimulate NGF production in astrocy tes. The effect of T-588 on Ca2+ reperfusion injury including apoptosis was inhibited by the mitogen-activated protein (MAP)/extracellular signal-regu lated kinase (ERK) kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059), b ut not by the phosphoinositide S-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 protect ive effects of T-588 and NGF. (C) 2000 Elsevier Science B.V. All rights res erved.