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 [Mg(2+)]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 [Ca(2+)]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 Ca(2+) 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.