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

Yang, Xin; Hamner, Margaret A.; Brown, Angus M.; Evans, Richard D.; Ye, Zu-Cheng; Chen, Shengdi; Ransom, Bruce R.

Abstract

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.

Citation

Yang, X., Hamner, M. A., Brown, A. M., Evans, R. D., Ye, Z., Chen, S., & Ransom, B. R. (2014). Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage. Annals of Neurology, 75(4), https://doi.org/10.1002/ana.24050

• Journal Article Type: Article
• Acceptance Date: Sep 27, 2013
• Online Publication Date: Mar 26, 2014
• Publication Date: Apr 10, 2014
• Deposit Date: Jul 25, 2016
• Publicly Available Date: Jul 25, 2016
• Journal: Annals of Neurology
• Print ISSN: 0364-5134
• Electronic ISSN: 0364-5134
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 75
• Issue: 4
• DOI: https://doi.org/10.1002/ana.24050
• Public URL: https://nottingham-repository.worktribe.com/output/727206
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1002/ana.24050/abstract
• 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 http://onlinelibrary.wiley.com/doi/10.1002/ana.24050/abstract. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.