Neuroprotective Effects of Increased Extracellular Ca²⁺ During Aglycemia in White Matter

Brown, Angus M., and Bruce R. Ransom.  Neuroprotective effects of increased extracellular Ca²⁺  during aglycemia in white matter. J Neurophysiol 88: 1302–1307, 2002; 10.1152/jn.00113.2002.  We investigated the effects of extracellular [Ca²⁺] ([Ca²⁺]_o) on aglycemia-induced dysfunction and injury in adult rat optic nerves. Compound action potentials (CAPs) from adult rat optic nerve were recorded in vitro, and the area under the CAP was used to monitor nerve function before and after 1 h periods of aglycemia. In control artificial cerebrospinal fluid (ACSF) containing 2 mM Ca²⁺, CAP function fell after 29.9 ± 1.5 (SE) min and recovered to 48.8 ± 3.9% following aglycemia. Reducing bath [Ca²⁺] during aglycemia progressively improved recovery. For example, in Ca²⁺-free ACSF, the CAP recovered to 99.1 ± 3.8%. Paradoxically, increasing bath [Ca²⁺] also improved recovery from aglycemia. In 5 or 10 mM bath [Ca²⁺], CAP recovered to 78.8 ± 9.2 or 91.6 ± 5.2%, respectively. The latency to CAP failure during aglycemia increased as a function of bath [Ca²⁺] from 0 to 10 mM. Increasing bath [Mg²⁺] from 2 to 5 or 10 mM, with bath [Ca²⁺] held at 2 mM, increased latency to CAP failure with aglycemia and improved recovery from this insult [Ca²⁺]_o recorded with calcium-sensitive microelectrodes in control ACSF, dropped reversibly during aglycemia from 1.54 ± 0.03 to 0.45 ± 0.04 mM. In the presence of higher ambient levels of bath [Ca²⁺] (i.e., 5 or 10 mM), the aglycemia-induced decrease in [Ca²⁺]_o declined, indicating that less Ca²⁺ left the extracellular space to enter an intracellular compartment. These results indicate that the role of [Ca²⁺], and divalent cations in general, during aglycemia is complex. While extracellular Ca²⁺ was required for irreversible aglycemic injury to occur, higher levels of [Ca²⁺] or [Mg²⁺] increased the latency to CAP failure and improved the extent of recovery, apparently by limiting Ca²⁺ influx. These effects are theorized to be mediated by divalent cation screening.