Lithium prevents and ameliorates experimental autoimmune encephalomyelitis

Patrizia De Sarno, Robert C. Axtell, Chander Raman, Kevin A. Roth, Dario R. Alessi, Richard S. Jope

    Research output: Contribution to journalArticle

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    Abstract

    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-gamma, 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.

    Original languageEnglish
    Pages (from-to)338-345
    Number of pages8
    JournalJournal of Immunology
    Volume181
    Issue number1
    Publication statusPublished - 1 Jul 2008

    Cite this

    De Sarno, P., Axtell, R. C., Raman, C., Roth, K. A., Alessi, D. R., & Jope, R. S. (2008). Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. Journal of Immunology, 181(1), 338-345.
    De Sarno, Patrizia ; Axtell, Robert C. ; Raman, Chander ; Roth, Kevin A. ; Alessi, Dario R. ; Jope, Richard S. / Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. In: Journal of Immunology. 2008 ; Vol. 181, No. 1. pp. 338-345.
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    abstract = "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-gamma, 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.",
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    De Sarno, P, Axtell, RC, Raman, C, Roth, KA, Alessi, DR & Jope, RS 2008, 'Lithium prevents and ameliorates experimental autoimmune encephalomyelitis', Journal of Immunology, vol. 181, no. 1, pp. 338-345.

    Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. / De Sarno, Patrizia; Axtell, Robert C.; Raman, Chander; Roth, Kevin A.; Alessi, Dario R.; Jope, Richard S.

    In: Journal of Immunology, Vol. 181, No. 1, 01.07.2008, p. 338-345.

    Research output: Contribution to journalArticle

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    AU - De Sarno, Patrizia

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    AB - 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-gamma, 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.

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    De Sarno P, Axtell RC, Raman C, Roth KA, Alessi DR, Jope RS. Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. Journal of Immunology. 2008 Jul 1;181(1):338-345.