QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 5, 2008, 28(10):2576-2588; doi:10.1523/JNEUROSCI.5467-07.2008

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Leng, Y. Articles by Chuang, D.-M. Search for Related Content PubMed PubMed Citation Articles by Leng, Y. Articles by Chuang, D.-M.

 Previous Article  |  Next Article 

Neurobiology of Disease
Synergistic Neuroprotective Effects of Lithium and Valproic Acid or Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition

Yan Leng, Min-Huei Liang, Ming Ren, Zoya Marinova, Peter Leeds, and De-Maw Chuang

Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363

Correspondence should be addressed to Dr. De-Maw Chuang, Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Room 3D-38, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363. Email: chuang{at}mail.nih.gov

Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar mood disorder and have frequently been used in combination to treat bipolar patients resistant to monotherapy with either drug. Lithium, a glycogen synthase kinase-3 (GSK-3) inhibitor, and VPA, a histone deacetylase (HDAC) inhibitor, have neuroprotective effects. The present study was undertaken to demonstrate synergistic neuroprotective effects when both drugs were coadministered. Pretreatment of aging cerebellar granule cells with lithium or VPA alone provided little or no neuroprotection against glutamate-induced cell death. However, copresence of both drugs resulted in complete blockade of glutamate excitotoxicity. Combined treatment with lithium and VPA potentiated serine phosphorylation of GSK-3 and β isoforms and inhibition of GSK-3 enzyme activity. Transfection with GSK-3 small interfering RNA (siRNA) and/or GSK-3β siRNA mimicked the ability of lithium to induce synergistic protection with VPA. HDAC1 siRNA or other HDAC inhibitors (phenylbutyrate, sodium butyrate or trichostatin A) also caused synergistic neuroprotection together with lithium. Moreover, combination of lithium and HDAC inhibitors potentiated β-catenin-dependent, Lef/Tcf-mediated transcriptional activity. An additive increase in GSK-3 serine phosphorylation was also observed in mice chronically treated with lithium and VPA. Together, for the first time, our results demonstrate synergistic neuroprotective effects of lithium and HDAC inhibitors and suggest that GSK-3 inhibition is a likely molecular target for the synergistic neuroprotection. Our results may have implications for the combined use of lithium and VPA in treating bipolar disorder. Additionally, combined use of both drugs may be warranted for clinical trials to treat glutamate-related neurodegenerative diseases.

Key words: lithium; valproic acid; HDAC inhibitors; neuroprotection; GSK-3; bipolar disorder

---

Received Aug. 8, 2007; revised Jan. 14, 2008; accepted Jan. 17, 2008.

Correspondence should be addressed to Dr. De-Maw Chuang, Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Room 3D-38, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363. Email: chuang{at}mail.nih.gov

This article has been cited by other articles:

				E. K. Murray, A. Hien, G. J. de Vries, and N. G. Forger Epigenetic Control of Sexual Differentiation of the Bed Nucleus of the Stria Terminalis Endocrinology, September 1, 2009; 150(9): 4241 - 4247. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help