White matter injury after brain ischemia

Ischemic white matter injury (WMI) is a significant concern in various clinical settings, particularly affecting the elderly and those with comorbidities such as hypoxia and hyperglycemia. Ischemic WMI can be caused either by primary WM ischemia, or secondary axonal injury as a result of the loss of the "remote" axonal parent neurons or the depletion of adhesive and neurotrophic molecules following post-synaptic neuronal death in the grey matter after focal ischemia. While neurons are highly vulnerable to ischemia, potentially undergoing cell death after an ischemic duration longer than a just few minutes, oligodendrocyte (OLG) lineage cells and axons show somewhat greater initial resistant to ischemia but ultimately suffer various degrees of damage after prolonged ischemia exposure. WMI typically progresses over time from initial demyelination to OLG death and axonal injury, followed by varying degrees of OLG biogenesis, remyelination, axonal sprouting, and synaptic reconnections. The severity of ischemic WMI is a key predictor of poor long-term outcome in brain ischemia-related conditions. Despite its clinical importance, ischemic WMI remains significantly understudied in preclinical animal models, creating a weak link in the field of ischemic brain injury animal research. Many molecular and pathological mechanisms underlying post-ischemic WMI remain poorly understood, and currently, no specific treatments exist for WMI patients. This review aims to stimulate WMI research by providing updated knowledge, emerging hypotheses, and future research directions to foster understanding the mechanisms and to guide the development of the effective therapeutic strategies.