Lovastatin attenuates nerve injury in an animal model of Guillain-Barré syndrome.
Statins, widely used as clinically effective inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, exhibit anti-inflammatory properties that may be of therapeutic benefit for the management of some neurological disorders. In this study, a short-term course of lovastatin treatment is shown to markedly inhibit the development of experimental autoimmune neuritis (EAN) in the absence of hepatotoxic or myotoxic complications. Independent of cholesterol reduction, lovastatin treatment prevented EAN-induced peripheral nerve conduction deficits and morphologic nerve injury. Co-administration with mevalonate neutralized the prophylactic effects of lovastatin. When administered therapeutically, lovastatin significantly shortened the disease course. Autoreactive immunity, measured in vitro by myelin-stimulated proliferation of splenocytes, was significantly diminished by in vivo lovastatin treatment. Th1-dominant immune responses, measured by cytokine profiling, however, were not affected by lovastatin. Sciatic nerves of lovastatin-treated immunized rats showed markedly reduced levels of cellular infiltrates. Treating peripheral nerve endothelial monolayers with lovastatin significantly inhibited the in vitro migration of autoreactive splenocytes. Together, these data demonstrate that a short-term course of lovastatin attenuates the development and progression of EAN in Lewis rats by limiting the proliferation and migration of autoreactive leukocytes.
Sarkey
Jason P
JP
Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, Illinois 60141, USA.
Richards
Michael P
MP
Stubbs
Evan B
EB
D000200:Action Potentials; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D018122:B7-1 Antigen / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D003402:Creatine Kinase / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020275:Guillain-Barre Syndrome / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008148:Lovastatin / Q000627:therapeutic use*; D008297:Male; D009431:Neural Conduction; D009443:Neuritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013154:Spleen / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018122:B7-1 Antigen; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase