Therapeutic effects of estrogens on inflammatory demyelination in a mouse model of multiple sclerosis

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disease in which the immune system targets the myelin sheath of nerve axons, leading to a variety of neurological signs. Sex hormones are thought to be important factors in MS since pregnancy and oral contraceptives reduce both symptoms and relapses. During pregnancy, remissions occur primarily in the third trimester when estradiol and estriol are elevated. We have investigated the role of these two hormones in an experimental model of virus-induced MS. Theiler's murine encephalomyelitis virus (TMEV) causes an inflammatory demyelinating disease in mice that resembles chronic progressive MS. To investigate the efficacy of estrogen therapy in the TMEV model, we used 6 experimental groups of 5-week-old female SJL/J mice. Mice were either infected with TMEV or were sham infected with PBS. At 15 weeks pi, during the chronic inflammatory disease, all mice were ovariectomized and implanted with slow-release pellets of either 1) vehicle 2) estradiol or 3) estriol. Weekly evaluation of clinical signs of disease revealed that estradiol treatment was associated with better clinical scores throughout the disease, and both treatment groups had significantly better scores than placebo (vehicle). At termination (24 weeks) we examined the percent demyelination and inflammation in spinal cords, and measured serum levels of TMEV antibodies, for all mice. Estradiol and estriol significantly decreased inflammation in the spinal cord, but only estradiol significantly decreased demyelination. Virus infection and hormone treatment each significantly affected levels of TMEV antibodies. Antibody levels also differed significantly between estradiol and placebo groups, and between estriol and placebo groups, for all mice regardless of infection status. These results suggest that estrogens may be effective therapies for progressive multiple sclerosis induced by viral infections.