Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels

Incidence, progression and severity of the multiple sclerosis, an inflammatory, demyelinating disease of the central nervous system (CNS) are affected in a sex-depending way. Physiological situations characterized by changes in sex steroid plasma levels, such as menstrual cycle, menopause or pregnancy, affect the disease course, suggesting that these molecules might exert a role in this disease. In order to understand better this possible relationship, we have here assessed the levels of neuroactive steroids present in different CNS regions of male and female rats affected by acute experimental autoimmune encephalomyelitis (EAE). In addition, we compared these levels with those present in plasma. Data obtained by liquid chromatography-tandem mass spectrometry indicate that the levels of neuroactive steroids show sex and regional differences in control and EAE nervous system and that a clear difference is also observed between CNS and plasma levels. In particular, among neuroactive steroids here considered, the levels of progesterone metabolites (i.e., dihydroprogesterone, tetrahydroprogesterone and isopregnanolone) and testosterone metabolites (i.e., dihydrotestosterone and 5alpha-androstane-3alpha17beta-diol), show sex dimorphic and region-specific changes in the CNS. Moreover, some changes observed in the CNS were not detected in plasma. These findings might represent an interesting background to design therapies and possibly sex-specific therapies for multiple sclerosis based on neuroactive steroids or synthetic ligands able to interact with classical and non-classical steroid receptors.