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Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death.
Neuropharmacology. 2005 Mar; 48(4):576-83.N

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 proapoptotic enzyme, glycogen synthase kinase-3 (GSK-3), has been 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-3-mediated apoptosis induced by trophic factor withdrawal (serum/potassium deprivation). Both lithium and indirubin, a specific GSK-3 inhibitor, protected CGNs in a dose-dependent manner. In contrast, VPA did not provide any neuroprotection and even potentiated cell death. Immunoblot analysis revealed that lithium inhibited the trophic factor deprivation-induced activation of GSK-3 as well as the in vivo phosphorylation of the microtubule-associated protein Tau on Ser199, a specific target site for GSK-3. Under these same experimental conditions, however, VPA neither inhibited GSK-3 activation nor hindered GSK-3 mediated Tau phosphorylation. Furthermore, in accordance with their effects on neuronal survival, lithium prevented the induction of c-Jun expression in trophic factor-deprived CGNs, whereas VPA potentiated it. Collectively, these results show that VPA is not a universal inhibitor of neuronal GSK-3, and that instead of being neuroprotective, VPA can even exacerbate neuronal death under some conditions.

Authors+Show Affiliations

Jin N
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA.
Kovács AD
No affiliation info available
Sui Z
No affiliation info available
Dewhurst S
No affiliation info available
Maggirwar SB
No affiliation info available

MeSH

AnimalsCell DeathCells, CulturedDose-Response Relationship, DrugEnzyme ActivationEnzyme InhibitorsGene Expression Regulation, EnzymologicGlycogen Synthase Kinase 3LithiumNerve Growth FactorsNeuronsProto-Oncogene Proteins c-junRatsRats, Sprague-DawleyValproic Acid

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15755485

Citation

Jin, Ning, et al. "Opposite Effects of Lithium and Valproic Acid On Trophic Factor Deprivation-induced Glycogen Synthase Kinase-3 Activation, c-Jun Expression and Neuronal Cell Death." Neuropharmacology, vol. 48, no. 4, 2005, pp. 576-83.
Jin N, Kovács AD, Sui Z, et al. Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death. Neuropharmacology. 2005;48(4):576-83.
Jin, N., Kovács, A. D., Sui, Z., Dewhurst, S., & Maggirwar, S. B. (2005). Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death. Neuropharmacology, 48(4), 576-83.
Jin N, et al. Opposite Effects of Lithium and Valproic Acid On Trophic Factor Deprivation-induced Glycogen Synthase Kinase-3 Activation, c-Jun Expression and Neuronal Cell Death. Neuropharmacology. 2005;48(4):576-83. PubMed PMID: 15755485.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death. AU - Jin,Ning, AU - Kovács,Attila D, AU - Sui,Ziye, AU - Dewhurst,Stephen, AU - Maggirwar,Sanjay B, Y1 - 2005/01/25/ PY - 2004/07/19/received PY - 2004/10/18/revised PY - 2004/11/27/accepted PY - 2005/3/10/pubmed PY - 2005/5/28/medline PY - 2005/3/10/entrez SP - 576 EP - 83 JF - Neuropharmacology JO - Neuropharmacology VL - 48 IS - 4 N2 - 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 proapoptotic enzyme, glycogen synthase kinase-3 (GSK-3), has been 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-3-mediated apoptosis induced by trophic factor withdrawal (serum/potassium deprivation). Both lithium and indirubin, a specific GSK-3 inhibitor, protected CGNs in a dose-dependent manner. In contrast, VPA did not provide any neuroprotection and even potentiated cell death. Immunoblot analysis revealed that lithium inhibited the trophic factor deprivation-induced activation of GSK-3 as well as the in vivo phosphorylation of the microtubule-associated protein Tau on Ser199, a specific target site for GSK-3. Under these same experimental conditions, however, VPA neither inhibited GSK-3 activation nor hindered GSK-3 mediated Tau phosphorylation. Furthermore, in accordance with their effects on neuronal survival, lithium prevented the induction of c-Jun expression in trophic factor-deprived CGNs, whereas VPA potentiated it. Collectively, these results show that VPA is not a universal inhibitor of neuronal GSK-3, and that instead of being neuroprotective, VPA can even exacerbate neuronal death under some conditions. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/15755485/Opposite_effects_of_lithium_and_valproic_acid_on_trophic_factor_deprivation_induced_glycogen_synthase_kinase_3_activation_c_Jun_expression_and_neuronal_cell_death_ DB - PRIME DP - Unbound Medicine ER -