Novel Hypoglycemic Injury Mechanism : N-Methyl-D-Aspartate Receptor–Mediated White Matter Damage

Objective: 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.
Methods: 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.
Results: 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 pH_o, expected results for NMDA receptor-mediated injury. pH _o 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). 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 pH_o caused by a fall in [lactate^-]_o. These insights have important clinical implications. Ann Neurol 2014;75:492-507 © 2014 American Neurological Association.