Stroke Literature Synopses: Basic Science

Doyle et al (Vesicular glutamate release from central axons contributes to myelin damage. Nat Commun. 2018;9:1032. doi: 10.1038/s41467-018-03427-1) examined the mechanisms as to how glutamate, a neurotransmitter that has an excitatory function, causes myelin damage after ischemic stress. Using a live 2-photon confocal imaging in mouse brain slices, the authors first showed that the primary source of vesicular glutamate release in the white matter (corpus callosum region) was axons. This mechanism was found to be triggered by ischemic stress, and a pharmacological approach indicated that the glutamate release was Ca-dependent but not because of the reverse of glutamate transporters. Then, the authors tested the efficacy of QNZ-46, which is an allosteric modulator of GluN2C/D-containing N-methyl-D-aspartate GluRs (glutamate receptors). Once QNZ-46 is incorporated into myelin through GluN2C/D-containing N-methyl-Daspartate GluRs, the drug is retained and negatively modulates GluN2C/D-containing N-methyl-D-aspartate GluRs. In ex vivo experiments using rat optic nerve axons and in in vivo mouse models of stroke (filament-model, 60-minute transient middle cerebral artery occlusion), pretreatment of QNZ-46 was shown to be protective for white matter against ischemic damage. Although QNZ-46 crossed the blood-brain barrier and was segregated into myelin, the systemic pretreatment of this drug did not induce any apparent behavioral deficits and acute toxicity. Therefore, these data provide a proof-of-concept that a selective myelin uptake/retention of a GluN2C/D N-methylD-aspartate receptor negative allosteric modulator may have therapeutic potential for patients at stroke risk.