Nitric oxide and aglycaemia induced axonal injury

Abstract

White matter degradation is known to lead to several neurological disorders. Recent unpublished data from our research group has shown that inducing injury through aglycaemia causes a rise in nitric oxide in white matter. The pathways for the generation of this NO are still unclear, but it is theorised that one possible source is from the overactivation of nNOS attached to NMDA receptors via the PSD95 domain. Aglycaemia-induced excitotoxicity results in a large influx of Ca2+ ions through NMDA receptors and thus results in white matter injury. In this study QNZ-46, a fluorescent drug which localises within the myelin sheets, was tested for its ability to inhibit the specific GluN2C/D-containing NMDA receptors found in the periaxonal space. NO production during aglycaemia was established in acute brain slices with live-imaging using 2-photon microscopy, and further confirmed through immunohistochemistry, where the endproduct of NO – nitrotyrosine – was detected both immediately after the insult, and at higher levels 2 hours after the insult. Application of QNZ-46 significantly lowers the initial spike in the production of NO following aglycaemia, thus confirming our hypothesis that it may offer protection to white matter from excitotoxicity-induced injury. Thus, our results suggests that QNZ-46, a non-toxic dose-dependent drug, may offer protection to neurological conditions in which excitotoxicity may induce white matter injury.