Injury to oligodendrocyte progenitors caused in part by glut

Injury to oligodendrocyte progenitors caused in part by glutamate contributes to the pathogenesis of myelination disturbances in PVL [5]. In the immature human brain, the susceptibility of developing oligodendrocytes to hypoxia-ischemia correlates with their expression of glutamate receptors of the AMPA receptor subtypes in the immature human brain [107], and systemic administration of AMPA receptor antagonists attenuates injury in a rat model of PVL [38]. In addition, developing oligodendrocytes also express NMDA receptors; their blockade with memantine attenuates oligodendrocyte loss and prevents the long-term reduction in cerebral mantle thickness that is observed in experimental PVL [60]. Ischemic injury to axons is also a feature of PVL; it occurs early in local and diffuse damage associated with this pathology [50]. Interestingly, experimental ischemia in immature axons produces Serdemetan failure and focal breakdown of the axolemma of small premyelinated axons at sites of contact with oligodendrocytic processes, which are also disrupted [2]. Axon damage is prevented by NMDA and AMPA/kainate receptor blockers, suggesting that glutamate receptor-mediated injury to oligodendrocytic processes in contact with premyelinated axons precedes disruption of the underlying axon [2]. Numerous studies conducted in cellular and animal models of multiple sclerosis (MS), as well as in post-mortem brain and in patients, have indicated that excitotoxicity mediated by Ca2+-permeable glutamate receptors contributes to oligodendrocyte death, demyelination, and tissue damage in MS [64,101,113]. In particular, EAE (experimental autoimmune encephalomyelitis), a mouse disease model that exhibits the clinical and pathological features of MS, is alleviated by AMPA and kainate receptor antagonists [80,99]. In contrast, blockade of NMDA receptors with MK-801 does not attenuate EAE symptoms [61]. Remarkably, blockade of these receptors in combination with anti-inflammatory agents is effective even at an advanced stage of unremitting EAE, as assessed by increased oligodendrocyte survival and remyelination, and corresponding decreased paralysis, inflammation, CNS apoptosis, and axonal damage [56]. Importantly, a genome-wide association screening study identified associated alleles in AMPA receptor genes in MS patients who exhibited the highest levels of glutamate and brain volume loss [8]. Glutamate levels are increased in the human brain [101] as a consequence of reduced expression of the glutamate transporters GLAST and GLT-1 [76,113]. Another mechanism accounting for glutamate dyshomeostasis is genetic variability in the promoter of the major glutamate transporter, GLT-1, which results in lower transporter expression [76]. In turn, upregulation of xCT in the monocyte-macrophage-microglia lineage is associated with immune activation in both MS and EAE [76]. Intriguingly, perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages as a consequence of elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation (reviewed in [21]). Thus, cerebral hypoperfusion in MS is associated with chronic hypoxia/ischemia that may underlie glutamate dyshomeostasis and excitotoxicity in that disease.
Axons: injury and glutamate release During ischemia, mature myelinated WM axons suffer cytotoxic Ca2+-influx via reverse Na-Ca exchange [104], an event triggered by Na+-influx mediated by non-inactivating voltage-gated Na+ channels [103]. Intracellular Ca2+-release contributes to Ca2+ overload in some myelinated axons [74,75], while voltage-gated Ca2+-channels are implicated as a significant alternative route of Ca2+ influx [35]. Myelinated axon expression of kainate and AMPA GluRs is significant for ischemic injury in large spinal cord axons [74,75], but distinguishing the significance of GluRs expressed by axon from those expressed on the closely apposed myelin sheath is difficult in other axon populations that are smaller in diameter. Over-activation of kainate- [62] or AMPA-type [39] GluRs in the optic nerve or external capsule respectively produces injury of the axon cylinder, and the protection afforded to axons by non-NMDA GluR antagonists is well-characterized (see [65]). However, non-NMDA GluR protein expression levels are generally low in axons, with much higher levels in neighbouring glial cells and myelin (including in humans [65]) and it is possible that the protection of myelinated axons by non-NMDA GluR antagonists is due to myelin protection and interruption of an injury pathway connecting myelin damage and subsequent axonal pathology [109]. Currently little is known about ischemic injury mechanisms in mature non-myelinated WM axons due to the technical challenge of recording from such small structures. The neonatal rodent optic nerve provides a preparation where pre-myelinated axon injury can be examined and NMDA GluR subunit expression has been documented in these axons where these receptors act as an important pathways for cytotoxic influx of Ca2+ and Na+ during modelled ischemia [2,51]. NMDA GluR expression has not been documented at latter developmental stages on myelinated axons but pre-myelinated and non-myelinated axons are phenotypically similar and the possibility remains that mature non-myelinated axons injury may involve axonal GluR expression to a greater degree than myelinated axons.