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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.

Authors

Xin Yang

Margaret A. Hamner

Angus M. Brown

Richard D. Evans

Zu-Cheng Ye

Shengdi Chen

Bruce R. Ransom



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 http://eprints.nottingham.ac.uk/id/eprint/35413
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/ana.24050/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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.wi...002/ana.24050/abstract. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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