Lithium prevents and ameliorates experimental autoimmune encephalomyelitis.
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 (MOG35-55) 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 MOG35-55-reactive effector T cell differentiation, greatly reducing in vitro MOG35-55- stimulated proliferation of mononuclear cells from draining lymph nodes and spleens, and MOG35-55-induced IFN-gamma, IL-6, and IL-17 production by splenocytes isolated from MOG35-55-immunized mice. In relapsing/remitting EAE induced with proteolipid protein peptide139-151, 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.
De Sarno
Patrizia
P
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, AL 35294, USA. desarno@uab.edu
Axtell
Robert C
RC
Raman
Chander
C
Roth
Kevin A
KA
Alessi
Dario R
DR
Jope
Richard S
RS
D000818:Animals; D000941:Antigens / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000941:Antigens; D008094:Lithium; D038362:Glycogen Synthase Kinase 3