Fig. 11.

Proposed model for hypoxic–ischemic injury pathways in cerebral white matter. Schematic shows myelinated axon (blue), oligodendrocytes (green), and astrocytes (red).A, Hypoxia, ischemia, or glucose deprivation results in energy depletion and loss of ATP. B, Failure of Na⁺/K⁺-ATPase and depolarization leads to opening of noninactivating axonal voltage-gated Na⁺ channels. Ca²⁺ enters axons by reversal of Na⁺/Ca²⁺ exchange and activation of voltage-gated Ca²⁺ channels. Action potentials are halted reversibly by loss of ionic gradients.C, Excessive axoplasmic Ca²⁺ levels trigger destructive pathways, leading to degradation of axonal cytoskeleton and organelles, focal axonal swelling, and eventual interruption of axonal integrity. D, Another effect of energy deprivation is release of glutamate into extracellular space (likely by reversal of Na⁺-dependent glutamate transport from axons and possibly astrocytes, oligodendrocytes). Glutamate activates ionotropic AMPA/KA receptors on oligodendrocytes (and possibly astrocytes). E, Sustained glutamate receptor activation triggers excitotoxic damage of oligodendrocyte processes (myelin) and subsequent death of oligodendrocytes. Myelin damage might result in conduction delay or block.F, Activation of glial AMPA/KA receptors or oligodendrocyte death triggers further damage to axons under energy-depleted conditions. Mechanisms linking glial glutamate receptors to axonal damage might include release of toxic substances from injured cells, increase in tissue energy use, loss of substrate or trophic support, exposure of protected membrane or ion channels, or failure of glial homeostatic functions. Blockade of stepD by NBQX protects oligodendrocytes and axons, whereas blockade of step B by TTX provides partial protection for axons, but not for oligodendrocytes. Other interactions are not shown. Ion homeostatic failure in axons may be responsible for glutamate release; Na⁺ removal and a blockade of Na⁺/Ca²⁺ exchange likely act on both axons and oligodendrocytes.