Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter

Abstract

Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors.

NMDA Receptor Blockade with Memantine Attenuates White Matter Injury in a Rat Model of Periventricular Leukomalacia

“…OLs in subcortical white matter brain slices in situ at P6, an age characterized by increased susceptibility to H/I injury (Follett et al, 2000), also express functional NMDARs, and these can be blocked by memantine. Supporting this observation, Bakiri et al (2008) recently reported that in P12 callosal white matter slices memantine reduced NMDA-evoked currents in MBP-positive mature OLs, and that the NMDAR antagonist D-AP5 reduced an ischemia-induced slowly developing inward current in both mature and developing OLs in vitro. Together, these results suggest that the direct blockade of NMDARmediated excitotoxicity intrinsic to OLs may contribute to the in vivo effect seen here.…”

“…Memantine, like MK-801, is an uncompetitive antagonist but exerts a use-dependent NMDAR blockade because of a faster off-rate than MK-801, and consequently exhibits less toxicity (Chen et al, 1992;Chen and Lipton, 2006). While this manuscript was under revision, a recent report emerged reporting protection of compound axon potentials from simulated ischemia in P28 rat myelinated optic nerve in vitro by memantine in combination with NBQX (Bakiri et al, 2008).…”

Glutamate receptor‐mediated ischemic injury of premyelinated central axons

“…Similar myelin expression in mature RON can mediate cytotoxic Ca 2+ influx [9][10][11] . As a result, NMDA receptors contribute to OGD-induced injury in this preparation 12 , although apparently not in mouse optic nerve 14,15 , and vesicular-and transporter-mediated glutamate release are potential sources of the extracellular glutamate responsible for GluR-mediated injury of oligodendrocyte processes described in the current study. Astrocytes may also act as a source of ischemic glutamate release in developing white matter 37,38 .…”

“…Similar expression in myelin is seen in mature rat optic nerve where it can mediate cytotoxic Ca 2+ influx [9][10][11] . Presumably as a result, NMDA receptors contribute to ischemic injury in myelinated rat optic nerve 12 , although no similar effect is found in mouse optic nerve 14,15 . .…”

“…The motor, sensory and cognitive deficits that characterize the lesion are associated with injury to immature cells of the oligodendroglial lineage, which are susceptible to a form of non-NMDA-type glutamate receptor (GluR) -mediated excitotoxic injury [3][4][5][6][7][8] . In addition to non-NMDA receptors, these cells express NMDA GluRs selectively on their processes [9][10][11] , although the role of NMDA receptors in ischemic injury of myelinated white matter is controversial [12][13][14][15] .…”