Opposite effects of lithium and valproic acid on trophic deprivation-induced GSK-3(Beta) activation, c-Jun expression and neuronal cell death

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Title: Opposite effects of lithium and valproic acid on trophic deprivation-induced GSK-3(Beta) activation, c-Jun expression and neuronal cell death
Author: Jin, Ning
Abstract: Recent studies demonstrate that lithium and valproic acid (VPA), two commonly used mood-stabilizing drugs, have neuroprotective effects against a variety of insults. Inhibition of the pro-apoptotic enzyme, glycogen synthase kinase-3P (GSK-3P), was suggested to be the mechanism of action of neuroprotection for both drugs. In this study, we tested if lithium and VPA could protect cultured cerebellar granule neurons (CGNs) from GSK-3P-mediated apoptosis induced by trophic withdrawal (serum/potassium deprivation). Lithium concentration-dependently (1-20 mM) protected CGNs. Indirubin, a specific, direct GSK-3P inhibitor, was also neuroprotective. On the contrary, VPA (1- 20 mM) did not provide any neuroprotection and even potentiated cell death. Immunoblot analysis revealed that lithium inhibited the trophic deprivation-induced activation of GSK-3P as well as the in vivo phosphorylation of Tau on Serl99, an exclusive target site for GSK-3p. Quite the opposite, VPA did neither inhibit GSK-3P activation nor hinder GSK-3p-mediated Tau phosphorylation. Besides GSK-3P activation, induction of the c- Jun stress response is also essential for apoptosis initiation in trophic deprived CGNs. Therefore we examined the effects of lithium and VPA on c-Jun expression following serum/potassium withdrawal. In accordance with the neuronal survival, lithium prevented the high increase in c-Jun expression, whereas VPA further elevated it. Altogether, our results show that VPA, unlike the common belief, is not a GSK-3 inhibitor and does not provide neuroprotection against GSK-3 P-mediated apoptosis.
Record URI: http://hdl.handle.net/1850/15047
Date: 2004-02

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