Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) characterized by encephalitogenic leukocyte infiltration and multifocal plaques of demyelination. Patients present with debilitating clinical sequelae including motor, sensory, and cognitive deficits. For the past 30 years, immune modulating treatments have entered the marketplace and continue to improve in limiting the frequency and severity of relapses, but no cure has been found and no drug has successfully stopped chronic progressive disease. Recent work focusing on the oligodendrocyte, the myelin-producing cell, has provided needed insight into the process of demyelination, the spontaneous ability of the CNS to regenerate, and the inevitable failure of remyelination. From this a number of promising molecular targets have been identified to protect oligodendrocytes and promote remyelination. Combining immunomodulatory therapy with strategies to protect oligodendrocytes from further degeneration and enhance remyelination presents a very real means to improve clinical outcome for chronic progressive patients in the near future. Here we lay out a combination therapy approach to treating MS and survey the current literature on promising drug candidates potentially capable of mediating oligodendrocyte protection and enhancing remyelination.

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Figure 1

Three therapeutic targets for combinatorial treatment strategies for multiple sclerosis. In the experimental autoimmune encephalomyelitis model of MS, CNS-infiltrating, autoreactive CD4+ T cells secrete cytokines that activate resident and infiltrating inflammatory immune cells leading to oligodendrocyte damage. The release of myelin antigens perpetuates the inflammatory process and subsequent oligodendrocyte destruction. The CNS is capable of significant regeneration. Endogenous oligodendrocyte progenitor cells (OPCs) proliferate, migrate to sites of inflammation, and differentiate to synthesize new myelin sheaths. To improve clinical outcome of MS patients we present three principal approaches: 1) halt pathologic immunity ideally by inhibiting antigen-specific responses rather than employing generalized immunosuppression, 2) protect oligodendrocytes from further damage, and 3) enhance remyelination either by transplanted exogenous cells or promote repair via endogenous OPCs.