Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor–mediated white matter damage
Article first published online: 26 MAR 2014
© 2014 American Neurological Association
Annals of Neurology
Volume 75, Issue 4, pages 492–507, April 2014
How to Cite
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
- Issue published online: 5 MAY 2014
- Article first published online: 26 MAR 2014
- Accepted manuscript online: 16 NOV 2013 06:33AM EST
- Manuscript Accepted: 27 SEP 2013
- Manuscript Revised: 29 AUG 2013
- Manuscript Received: 10 MAY 2013
Hypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined whether glutamate receptors were involved in hypoglycemic WM injury.
Mouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebrospinal fluid (ACSF) containing 10mM glucose. Aglycemia was produced by switching to 0 glucose ACSF. Supramaximal 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 high-performance liquid chromatography. Extracellular lactate concentration ([lactate−]o) was measured using an enzyme electrode.
About 50% of MON axons were injured after 60 minutes of aglycemia (90% after 90 minutes); injury extent was not affected by animal age. Blockade of N-methyl-D-aspartate (NMDA)-type glutamate receptors improved recovery after 90 minutes 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. pHo 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 ([glutamate]o fell).
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. Ann Neurol 2014;75:492–507