Targeting oligodendrocyte protection and remyelination in multiple sclerosis

Abstract

Multiple sclerosis is an inflammatory demyelinating disease of the brain and spinal cord with a presumed autoimmune etiology. Conduction block in demyelinated axons underlies early neurological symptoms, whereas axonal transection is believed responsible for more permanent later deficits. Approved treatments for the disease are immunoregulatory and reduce the rate of lesion formation and clinical exacerbation, but are only partially effective in preventing the onset of disability in multiple sclerosis patients. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes and reduce the rate of axonal transection. Studies in genetically modified animals have improved our understanding of mechanisms underlying central nervous system pathology in multiple sclerosis models, and have identified pathways that regulate oligodendrocyte viability and myelin repair. However, although clinical trials are ongoing, many have been unsuccessful, and no treatments are yet approved that target these areas in multiple sclerosis. In this review, we examine avenues for oligodendrocyte protection and endogenous myelin repair in animal models of demyelination and remyelination, and their relevance as therapeutics in human patients.

Figure 1. Factors regulating oligodendrocyte lineage proliferation, maturation and death

This schematic outlines the progression of oligodendrocyte maturation, from unspecified neural progenitors (top), through specified oligodendrocyte progenitors, to mature postmitotic cells that enter the myelination program (bottom). Illustrated are the mechanisms of action within this system of factors that increase (right side of panel) or decrease (left side) the numbers of mature myelinating oligodendrocytes. The neurotrophin NT-3, the gp130 cytokines CNTF, IL-11 and LIF, and the insulin-like growth factor IGF-1 (right side of panel) all increase the viability of mature oligodendrocytes or their precursors. Additionally, NT-3 potentiates precursor proliferation, whereas gp130 cytokines promote differentiation. Neuregulin 1 type III-ErbB signaling facilitates axonal ensheathment and myelin wrapping. Conversely, bone morphogenetic proteins (left side of panel) inhibit oligodendrocyte lineage specification and subsequent progenitor differentiation. Canonical Notch and Wnt signaling restrict oligodendrocyte maturation and maintain the size of the progenitor pool.