The Role of alpha 4 Integrins on Theiler's Murine Encephalomyelitis Virus (TMEV)-Induced Demyelinating Disease, An Infectious Animal Model for Multiple Sclerosis (MS)

Natalizumab, which is an antibody against alpha 4 integrin, has been used for the treatment of multiple sclerosis. In the present study, we investigated both the role of alpha 4 integrin and the therapeutic effect of HCA3551, a newly synthesized orally active small molecule alpha 4 integrin antagonist, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). The mRNA levels of alpha 4 integrins were significantly up-regulated in the central nervous system (CNS) of mice with TMEV-IDD as compared with naive mice (*P < 0.05). HCA3551 treatment in the effector phase significantly suppressed both the clinical and histological development of TMEV-IDD. The number of infiltrating mononuclear inflammatory cells in the CNS was significantly decreased in the mice treated with HCA3551 (**P < 0.01). The labeling indices for CD68 antigen and the absolute cell numbers of TNF-alpha-producing CD4(+) T cells and IFN-gamma-producing CD8(+) T cells were significantly decreased in the CNS of mice treated with HCA3551 (*P < 0.05). HCA3551 treatment in the effector phase might inhibit the binding of alpha 4 integrin to vascular cell adhesion molecule-1, thereby decreasing the number of mononuclear cells in the CNS.