The pathophysiology of anoxic injury in central nervous system white matter

White matter of the mammalian brain is susceptible to anoxic injury, but little is knwon about the pathophysiology of this process. We studied the mechanisms of anoxic injury in white matter using the isolated rat optic nerve, a typical central nervous system white-matter tract. Optic nerve function, measured as the area under the compound action potential, rapidly failed when exposed to anoxia. Postanoxic recovery was variable, depending on duration of the anoxic insult; after a standard 60-minute period of anoxia, the compound action potential recovered to 28.5% of control. Irreversible anoxic injury was critically dependent on extracellular Ca²⁺; maintaining the tissue in zero [Ca²⁺] solution throughout the anoxic period resulted in 100% compound action potential recovery. Increasing perfusate [Ca²⁺] during anoxia from zero to 4 mM resulted in progressively less recovery. Anoxic damage to the optic nerve appears to depend on the gradual accumulation (over tens of minutes) of Ca²⁺ in a cytoplasmic compartment. The inorganic Ca²⁺ channel blockers Mn²⁺ (1 mM), Co²⁺ (1 mM), or La³⁺ (0.1 mM) had no effect on recovery of the compound action potential after anoxia; only Mg²⁺ (10 mM) significnatly improved recovery. Treatment with the dihydropyridine Ca²⁺ channel blockers nifedipine (1-10 μM) or nimodipine (1-40 μM) also had no effect on recovery from anoxia. Thus, Ca²⁺ influx during anoxia does not occur via conventional Ca²⁺ channels. Preliminary evidence suggests that this Ca²⁺ influx may occur via other cation channels that are imperfectly selective for Ca²⁺ or via the Na⁺-Ca²⁺ exchanger. Ketamine (1 mM), a dissociative anesthetic known to block N-methyl-D-aspartate receptors and reduce hypoxic injury in gray matter, imporved compound action potential recovery after anoxia. Because glutamate and asparatate (up to 10 mM) were not toxic to the optic nerve, the beneficial effect of ketamine on white matter recovery probably is not mediated by N-methyl-D-aspartate receptor blockade.