title: Ionic mechanisms of aglycemic axon injury in mammalian central white matter.
abstract: The authors investigated ionic mechanisms underlying aglycemic axon injury in adult rat optic nerve, a central white matter tract. Axon function was assessed using evoked compound action potentials (CAPs). Glucose withdrawal led to delayed CAP failure, an alkaline extracellular pH shift, and an increase in extracellular [K(+)]. Sixty minutes of glucose withdrawal led to irreversible axon injury. Aglycemic axon injury required extracellular calcium; the extent of injury progressively declined as bath [Ca(2+)] was decreased. To evaluate Ca(2+) movements during aglycemia, the authors recorded extracellular [Ca(2+)] ([Ca(2+)](o)) using Ca(2+)-sensitive microelectrodes. Under control conditions, [Ca(2+)](o) fell with a similar time course to CAP failure, indicating extracellular Ca(2+) moved to an intracellular position during aglycemia. The authors quantified the magnitude of [Ca(2+)]o decrease as the area below baseline [Ca(2+)]o during aglycemia and used this as a qualitative measure of Ca(2+) influx. The authors studied the mechanisms of Ca(2+) influx. Blockade of Na(+) influx reduced Ca(2+) influx and improved CAP recovery, suggesting Na(+)-Ca(2+) exchanger involvement. Consistent with this hypothesis, bepridil reduced axon injury. In addition, diltiazem or nifedipine decreased Ca(2+) influx and increased CAP recovery. The authors conclude aglycemic central white matter injury is caused by Ca(2+) influx into intracellular compartments through reverse Na(+)-Ca(2+) exchange and L-type Ca(2+) channels.
authors.affiliation: Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Brown
authors.forename: R
authors.initials: R
authors.lastname: Wender
authors.forename: B R
authors.initials: BR
authors.lastname: Ransom
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D015764:Bepridil / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004110:Diltiazem / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000494:pharmacology; D008322:Mammals; D009543:Nifedipine / Q000494:pharmacology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D019831:Sodium-Calcium Exchanger; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015764:Bepridil; D012964:Sodium; D004110:Diltiazem; D007736:Kynurenic Acid; D009543:Nifedipine; D005947:Glucose; D002118:Calcium