Oligodendrocyte pathophysiology and treatment strategies in cerebral ischemia

Abstract

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, form a functional unit with axons and play a crucial role in axonal integrity. An episode of hypoxia-ischemia causes rapid and severe damage to these particularly vulnerable cells via multiple pathways such as overactivation of glutamate and ATP receptors, oxidative stress, and disruption of mitochondrial function. The cardinal effect of OL pathology is demyelination and dysmyelination, and this has profound effects on axonal function, transport, structure, metabolism, and survival. The OL is a primary target of ischemia in adult-onset stroke and especially in periventricular leukomalacia and should be considered as a primary therapeutic target in these conditions. More emphasis is needed on therapeutic strategies that target OLs, myelin, and their receptors, as these have the potential to significantly attenuate white matter injury and to establish functional recovery of white matter after stroke. In this review, we will summarize recent progress on the role of OLs in white matter ischemic injury and the current and emerging principles that form the basis for protective strategies against OL death.

Keywords: Excitotoxicity; Hypoxia-ischemia; Oligodendrocyte; Oxidative stress; White matter.

Figure 1

Features of oligodendrocytes (OLs) and pre‐OLs which render them vulnerable to hypoxia–ischemia (HI). The amplified vulnerability of OLs to HI derives from their high iron content, low reduced glutathione content, high rate of oxidative metabolism, high lipid and sphingolipid content, and high permeability of glutamate receptors. Pre‐OLs are even more vulnerable than their mature counterparts due to low levels of antioxidant enzymes, upregulation of AMPA/kainate receptors and enhanced AMPA/kainate signaling, increased expression of the glutamate transporter EAAT2, and a susceptibility to direct mitochondrial toxicity by reactive nitrogen species. In the event of HI, these properties lead to higher levels of oxidative stress and apoptosis, hence, severe damage, and death to cells of this lineage.

Figure 2

The major pathways governing neurotransmitter‐mediated oligodendrocyte death in hypoxia–ischemia (HI). The glutamate surge that occurs during HI leads to the overactivation of AMPA/kainate receptors on oligodendrocyte somata and NMDA receptors on myelinating processes. ATP is also released in HI, partly from the oligodendrocyte itself via pannexin hemichannels, leading to the overactivation of purinergic P2X7 receptors and enhanced Ca²⁺ signaling. The Ca²⁺ surge leads to the activation of voltage‐gated calcium channels (VGCC) and reversal of Na⁺/Ca²⁺ exchanger (NCX), further increasing the intracellular Ca²⁺. The glutamate transporter EAAT2 also starts to operate in reverse, contributing to the surge in extracellular glutamate. The excess cytosolic Ca²⁺ is sequestered in mitochondria where it leads to mitochondrial disruption and oxidative stress and eventual death to oligodendrocytes.