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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dc.contributor.advisor Maggirwar, Sanjay
dc.contributor.author Jin, Ning
dc.date.accessioned 2012-05-23T14:57:37Z
dc.date.available 2012-05-23T14:57:37Z
dc.date.issued 2004-02
dc.identifier.uri http://hdl.handle.net/1850/15047
dc.description.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. en_US
dc.language.iso en_US en_US
dc.relation RIT Scholars content from RIT Digital Media Library has moved from http://ritdml.rit.edu/handle/1850/15047 to RIT Scholar Works http://scholarworks.rit.edu/theses/2730, please update your feeds & links!
dc.subject Clinical chemistry en_US
dc.subject.lcc QH671 .J56 2004
dc.subject.lcsh Apoptosis--Prevention--Research en_US
dc.subject.lcsh Lithium--Physiological effect--Research en_US
dc.subject.lcsh Valproic acid--Physiological effect--Research en_US
dc.subject.lcsh Cerebellar nuclei en_US
dc.subject.lcsh Phosphorylation en_US
dc.subject.lcsh Cerebellum--Degeneration--Chemoprevention--Research en_US
dc.title Opposite effects of lithium and valproic acid on trophic deprivation-induced GSK-3(Beta) activation, c-Jun expression and neuronal cell death en_US
dc.type Thesis en_US
dc.description.college College of Science en_US
dc.description.department Department of Medical Sciences en_US

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