HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by De Sarno, P. Articles by Jope, R. S. PubMed PubMed Citation Articles by De Sarno, P. Articles by Jope, R. S.

Lithium Prevents and Ameliorates Experimental Autoimmune Encephalomyelitis¹

Patrizia De Sarno^2,*, Robert C. Axtell^3,, Chander Raman, Kevin A. Roth, Dario R. Alessi and Richard S. Jope^2,*

^* Department of Psychiatry and Behavioral Neurobiology, Department of Medicine, and Department of Pathology, University of Alabama, Birmingham, AL 35294; and Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom

Experimental autoimmune encephalomyelitis (EAE) models, in animals, many characteristics of multiple sclerosis, for which there is no adequate therapy. We investigated whether lithium, an inhibitor of glycogen synthase kinase-3 (GSK3), can ameliorate EAE in mice. Pretreatment with lithium markedly suppressed the clinical symptoms of EAE induced in mice by myelin oligodendrocyte glycoprotein peptide (MOG_35–55) immunization and greatly reduced demyelination, microglia activation, and leukocyte infiltration in the spinal cord. Lithium administered postimmunization, after disease onset, reduced disease severity and facilitated partial recovery. Conversely, in knock-in mice expressing constitutively active GSK3, EAE developed more rapidly and was more severe. In vivo lithium therapy suppressed MOG_35–55-reactive effector T cell differentiation, greatly reducing in vitro MOG_35–55- stimulated proliferation of mononuclear cells from draining lymph nodes and spleens, and MOG_35–55-induced IFN-, IL-6, and IL-17 production by splenocytes isolated from MOG_35–55-immunized mice. In relapsing/remitting EAE induced with proteolipid protein peptide_139–151, lithium administered after the first clinical episode maintained long-term (90 days after immunization) protection, and after lithium withdrawal the disease rapidly relapsed. These results demonstrate that lithium suppresses EAE and identify GSK3 as a new target for inhibition that may be useful for therapeutic intervention of multiple sclerosis and other autoimmune and inflammatory diseases afflicting the CNS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Multiple Sclerosis Society PP1335 (to P.D.), RG3891A1 (to C.R.), and National Institute of Health Grants MH38752 and NS37768 (to R.S.J.).

² Address correspondence and reprint requests to Dr. Richard S. Jope and Dr. Patrizia De Sarno, Department of Psychiatry and Behavioral Neurobiology, University of Alabama, 1720 Seventh Avenue South, Birmingham, AL 35294. E-mail addresses: jope{at}uab.edu and desarno{at}uab.edu

³ Current address: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305.

⁴ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein peptide; GSK3, glycogen synthase kinase-3; CDI, cumulative disease index; Treg, T regulatory.

This article has been cited by other articles:

				J.-M. Beaulieu and M. G. Caron Looking at Lithium: Molecular Moods and Complex Behaviour Mol. Interv., October 1, 2008; 8(5): 230 - 241. [Abstract] [Full Text] [PDF]