White matter injury: Ischemic and nonischemic

• Published in: Glia Vol. 62; no. 11; pp. 1780 - 1789
• Main Authors: Fern, Robert F., Matute, Carlos, Stys, Peter K.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2014; Wiley Subscription Services, Inc
• Subjects: Animals; Astrocyte; ATP; Axon; Axons - pathology; Brain damage; Brain Ischemia - complications; Glutamate; Humans; Ischemia; Leukoencephalopathies - etiology; Leukoencephalopathies - pathology; Neuroglia - pathology; Neurotransmitter Agents - metabolism; Oligodendrocyte; Pathology; Protein expression; Axon; Astrocyte; Oligodendrocyte; Glutamate; ATP
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22722

Ischemic pathologies of white matter (WM) include a large proportion of stroke and developmental lesions while multiple sclerosis (MS) is the archetype nonischemic pathology. Growing evidence suggests other important diseases including neurodegenerative and psychiatric disorders also involve a significant WM component. Axonal, oligodendroglial, and astroglial damage proceed via distinct mechanisms in ischemic WM and these mechanisms evolve dramatically with maturation. Axons may pass through four developmental stages where the pattern of membrane protein expression influences how the structure responds to ischemia; WM astrocytes pass through at least two and differ significantly in their ischemia tolerance from grey matter astrocytes; oligodendroglia pass through at least three, with the highly ischemia intolerant pre‐oligodendrocyte (pre‐Oli) stage linking the less sensitive precursor and mature phenotypes. Neurotransmitters play a central role in WM pathology at all ages. Glutamate excitotoxicity in WM has both necrotic and apoptotic components; the latter mediated by intracellular pathways which differ between receptor types. ATP excitotoxicity may be largely mediated by the P2X7 receptor and also has both necrotic and apoptotic components. Interplay between microglia and other cell types is a critical element in the injury process. A growing appreciation of the significance of WM injury for nonischemic neurological disorders is currently stimulating research into mechanisms; with curious similarities being found with those operating during ischemia. A good example is traumatic brain injury, where axonal pathology can proceed via almost identical pathways to those described during acute ischemia. GLIA 2014;62:1780–1789 Main Points: Ischemic pathologies of central white matter include a large stroke and developmental lesions; multiple sclerosis is an archetype non-ischemic white matter pathology. Axon, oligodendroglial and astroglial damage are all features of ischemic injury and the cellular mechanisms vary greatly between these and evolve dramatically with maturation. Axons may pass through four stages where the pattern of membrane protein expression dictates how the structure responses to ischemic conditions; astrocytes pass through two; oligodendroglial pass through at three. Glutamate excitotoxicity in WM has both necrotic and apoptotic components; the later mediated by distinct intracellular pathways which differ between receptor types. ATP excitotoxicity may be largely mediated by the P2X7 receptor and also has both necrotic and apoptotic components, and interplay between microglia and other cell types is a critical element in the injury process. A growing appreciation of the significance of WM injury for non-ischemic neurological disorders is currently stimulating research into mechanisms; with curious similarities being found with those operating during ischemia. A good example is traumatic brain injury, where axonal pathology can proceed via almost identical pathways to those described during acute ischemia.