Tropisetron diminishes demyelination and disease severity in an animal model of multiple sclerosis

Abstract

Tropisetron, a selective 5-HT3 receptor (5-HT3R) antagonist, has been widely used to counteract chemotherapy-induced emesis. New investigations described the immunomodulatory properties of tropisetron which may not be 5HT3R mediated. In the present study, we assessed the potential effects of tropisetron on an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). EAE was induced in C57BL/6 mice by myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization. Animals were treated with tropisetron (5 mg/kg/day); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3R agonist (10 mg/kg/day); tropisetron (5 mg/kg/day) plus mCPBG (10 mg/kg/day), and granisetron (5 mg/kg/day) intraperitoneally on days 3-35 post-immunization. Treatment with tropisetron and granisetron markedly suppressed the clinical symptoms of EAE (p<0.001) and reduced leukocyte infiltration as well as demyelination in the spinal cord (p<0.05). In addition, in vivo tropisetron, granisetron or tropisetron plus mCPBG therapy greatly reduced in vitro MOG35-55-stimulated proliferation of mononuclear cells from spleens, and MOG35-55-induced IL-2, IL-6 and IL-17 production by splenocytes isolated from EAE-induced mice (p<0.05). Concurrent administration of tropisetron and mCPBG did not significantly alter the histological damage in the spinal cord. mCPBG had no effect on the mentioned parameters. Taken together, these findings indicate that tropisetron has considerable immunoregulatory functions in EAE and may be promising for the treatment of MS or other autoimmune and inflammatory diseases of the CNS. Furthermore, beneficial effects of tropisetron in this setting seem to be both receptor dependent and receptor independent in the early phase of the disease.

Keywords: 5-HT3 receptor; experimental autoimmune encephalomyelitis; multiple sclerosis; tropisetron.