White matter injury: Ischemic and nonischemic

Abstract

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.

Action Potential Firing Induces Sodium Transients in Macroglial Cells of the Mouse Corpus Callosum

“…After slice preparation, the tissue was kept at 34 • C for 20 min in saline containing 0.5-1 µM sulforhodamine 101 (SR101) for specific labelling of astrocytes [38]. Afterwards, slices were incubated in SR101-free saline and kept at room temperature (20)(21)(22) • C). Experiments were performed at room temperature as well.…”

“…While white matter tracts do not feature classical chemical synapses between neurons, axons can release glutamate in an activity-dependent manner (e.g., [16][17][18][19]). It is also established that white matter macroglia express sodium-dependent glutamate transporters, which are especially important to protect the tissue from glutamate-induced excitotoxicity [20][21][22][23][24]. In line with this, we could recently demonstrate that application of glutamate results in sodium transients in astrocytes and cells of the oligodendroglial lineage (representing mature oligodendrocytes as well as NG2 cells) in tissue slices of corpus callosum of the mouse, which were strongly dampened upon pharmacological inhibition of glutamate uptake in both groups [25].…”

Neuroprotective therapies for multiple sclerosis and other demyelinating diseases

“…Excitotoxicity is postulated as the prime mechanism of damage in epilepsy and it has also been associated with neurodegenerative diseases as well with MS [41,42]. By over-activating the excitatory glutamate receptors, neurons experience high levels of electrical and energetic activity, inducing ion imbalance and promoting neuronal death.…”

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes

“…The specific region in which cells have died (called the 'core') is surrounded by an area in which intermediate perfusion prevails (called the 'penumbra'), and the cells in penumbra depolarize sporadically [3]. The majority of studies examining cell death following cerebral ischemia have focused on neurons, but a recent work indicates that ischemia also causes both activation of and damage to the glia [4]. Astrocytes comprise about 50% of brain cells and support neurons structurally, metabolically, and trophically.…”