Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage

Abstract

An influx of extracellular Ca²⁺ , with subsequent cellular Ca²⁺ overload, can clearly cause certain types of cell death, and has been hypothesized to be a primary etiological event in hypoxic-ischemic neuronal injury. Recently, this hypothesis has acquired new specificity, as hypoxic-ischemic neuronal injury has been linked to the excessive activation of postsynaptic glutamate receptors, and glutamate neurotoxicity itself has been linked to a lethal influx of extracellular Ca²⁺ through cell membrane channels. Available data suggest that channels gated by the $\text{N-}\text{methyl-}\text{d}\text{-aspartate}$ (NMDA) subclass of glutamate receptors may be the predominant route of glutamate- or hypoxia-induced lethal Ca²⁺ entry; however, other routes, including L- and N-type voltage-gated Ca²⁺ channels, the Na⁺/Ca²⁺ exchanger, and non-specific membrane leak, may also participate. Current efforts to develop an effective therapy for hypoxic-ischemic neuronal injury are appropriately focused on NMDA antagonists; however, it is possible that additional benefit might be gained by combining NMDA antagonists with pharmacological manipulations designed to attenuate Ca²⁺ entry through these other routes.