Influence of neurosteroids on the pathogenesis of multiple sclerosis

Abstract

This paper summarizes neuroendocrine effects on myelination and their possible relevance for the pathogenesis of multiple sclerosis (MS). Steroid hormones known as neurosteroids are synthesized in the human central nervous system (CNS) and exert local effects on glial and neuronal tissue. Progesterone derivatives seem to act as promyelinating factors in the slow but continuous process of myelin maintenance in the adult human brain. Diminished production of these myelin-promoting factors may lead to the formation of structurally altered and less stable myelin, resulting in the observed pathology of the normal-appearing white matter (NAWM) in MS. Dysmyelination, characterized by an altered myelin protein composition, reduced myelin content and increased vulnerability of the myelin sheath, precedes the formation of inflammatory lesions and the clinical onset of disease. Defects in the myelin sheath first occur in mechanically strained areas of the brain, where myelin turnover is physiologically increased. The continuous exposure of myelin proteins, normally sheltered from immunosurveillance, will lead to microglia activation and phagocytosis of myelin. Phagocytic cells from the brain and myelin material may drain to cervical lymph nodes with subsequent priming of T-cells. Finally, heterogenous focal auto-inflammatory reactions contribute to the clinical symptoms of the disease. Neurosteroids influence the biochemical composition of myelin proteins and promote myelin renewal. These promyelinating neurosteroidal functions seem to be impaired in the MS brain. Contrary to the view of auto-inflammatory demyelination being a causative factor in MS pathogenesis, it is argued here that widespread dysmyelination in the adult human brain precedes and induces a focal immune response to various myelin compounds.