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 [Ca2+] was decreased. To evaluate Ca2+ movements during aglycemia, the authors recorded extracellular [Ca2+] ([Ca2+]o) using Ca2+-sensitive microelectrodes. Under control conditions, [Ca2+]o fell with a similar time course to CAP failure, indicating extracellular Ca2+ moved to an intracellular position during aglycemia. The authors quantified the magnitude of [Ca2+]o decrease as the area below baseline [Ca2+]o during aglycemia and used this as a qualitative measure of Ca2+ influx. The authors studied the mechanisms of Ca2+ influx. Blockade of Na+ influx reduced Ca2+ influx and improved CAP recovery, suggesting Na+-Ca2+ exchanger involvement. Consistent with this hypothesis, bepridil reduced axon injury. In addition, diltiazem or nifedipine decreased Ca2+ influx and increased CAP recovery. The authors conclude aglycemic central white matter injury is caused by Ca2+ influx into intracellular compartments through reverse Na+-Ca2+ exchange and L-type Ca2+ channels.