Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage

Yang, Xin and Hamner, Margaret A. and Brown, Angus M. and Evans, Richard D. and Ye, Zu-Cheng and Chen, Shengdi and Ransom, Bruce R. (2014) Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage. Annals of Neurology, 75 (4). pp. 492-507. ISSN 0364-5134

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Objective: Hypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined if glutamate receptors were involved in hypoglycemic WM injury.

Methods: Mouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebrospinal fluid (ACSF) containing 10 mM glucose. Aglycemia was produced by switching to 0 glucose ACSF. Supra-maximal compound action potentials (CAPs) were elicited using suction electrodes and axon function was quantified as the area under the CAP. Amino acid release was measured using HPLC. Extracellular [lactate] was measured using an enzyme electrode.

Results: About 50% of MON axons were injured after 60 min of aglycemia (90% after 90 min); injury was not affected by animal age. Blockade of NMDA-type glutamate receptors improved recovery after 90 min of aglycemia by 250%. Aglycemic injury was increased by reducing [Mg2+]o or increasing [glycine]o, and decreased by lowering pHo, expected results for NMDA receptor-mediated injury. Extracellular pH increased during aglycemia, due to a drop in [lactate-]o. Aglycemic injury was dramatically reduced in the absence of [Ca2+]o. Extracellular aspartate, a selective NMDA receptor agonist, increased during aglycemia.

Interpretation: Aglycemia injured WM by a unique excitotoxic mechanism involving NMDA receptors (located primarily on oligodendrocytes). During WM aglycemia, the selective NMDA agonist, aspartate, is released, probably from astrocytes. Injury is mediated by Ca2+ influx through aspartate-activated NMDA receptors made permeable by an accompanying alkaline shift in pHo caused by a fall in [lactate-]o. These insights have important clinical implications.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: Yang, X., Hamner, M. A., Brown, A. M., Evans, R. D., Ye, Z.-C., Chen, S. and Ransom, B. R. (2014), Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor–mediated white matter damage. Ann Neurol., 75: 492–507. doi: 10.1002/ana.24050, which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Biomedical Sciences
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Depositing User: Eprints, Support
Date Deposited: 25 Jul 2016 14:02
Last Modified: 24 Sep 2016 16:47

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