Demyelination as a rational therapeutic target for ischemic or traumatic brain injury

Abstract

Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients.

Keywords: Cerebral ischemia; Demyelination; Oligodendrocyte; Remyelination; Traumatic brain injury.

Figure 1. Astrocyte, oligodendrocyte, and axon interactions in white matter in normal or pathological settings

Under normal conditions, astrocytes take up glucose from capillaries through glucose transporters (GLUTs) and the subsequent glycolysis metabolites can be transmitted to axons and oligodendrocytes as energy sources by monocarboxylic acid transporters (MCTs) and connexins (CXs). However, when astrocytes are activated under stressful conditions, the normal CX-mediated communication between astrocytes and oligodendrocytes is interrupted, resulting in oligodendrocyte cell death and subsequent demyelination.

Figure 2. Microglial activation after stroke or TBI

After stroke or TBI, resting microglia are polarized toward the M1 or M2 phenotype. M1 microglia release multiple pro-inflammatory cytokines, leading to cell damage and exacerbate brain injury. However, M2 microglia secrete anti-inflammatory cytokines and growth factors, contributing to tissue repair.