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 IKK Inhibitor VII 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.