Sex steroids, neurosteroidogenesis, and inflammation in multiple sclerosis and related animal models

Multiple sclerosis (MS) and rodent models of the disease including experimental autoimmune encephalomyelitis, cuprizone intoxication, and lysophosphatidyl choline-induced demyelination show altered levels of circulating sex steroids and changes in the biosynthesis of nervous system localized steroidogenesis (neurosteroidogenesis). Therapy with progesterone, estrogens, androgens, or direct stimulation of neurosteroidogenesis shows beneficial effects for brain and spinal cord neuropathology of MS models owing to the reduction of reactive astrocytes and microglia, downregulation of the expression of proinflammatory markers, improved myelin formation from oligodendrocyte precursors, and better clinical scores and behavioral performances. Steroid effectiveness is explained in part by activation of classical nuclear receptors, membrane receptors, and modulation of gamma aminobutyric acid (GABAA) receptors expressed by several cell types from different central nervous system (CNS) regions. Because resolving inflammation is crucial for treatment of MS and related animal models, treatment with natural or synthetic steroids or with molecules targeting neurosteroidogenesis may open further therapeutic opportunities for neuroinflammatory diseases.