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).


CONCLUSIONS
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.
Department of Neurology, Ruijin Hospital, affiliated with Shanghai Jiaotong University School of Medicine, Shanghai, China.
Xin
X
Yang
Margaret A
MA
Hamner
Angus M
AM
Brown
Richard D
RD
Evans
Zu-Cheng
ZC
Ye
Shengdi
S
Chen
Bruce R
BR
Ransom
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007003:Hypoglycemia / Q000150:complications; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D019344:Lactic Acid / Q000378:metabolism; D056784:Leukoencephalopathies / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D011810:Quinoxalines / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001224:Aspartic Acid; D019344:Lactic Acid; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D006003:Glycogen; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D002118:Calcium; D005998:Glycine