Calcium and the pathogenesis of traumatic CNS injury: Cellular and molecular mechanisms

Under normal conditions in the central nervous system (CNS), the calcium ion (Ca²⁺) is known to mediate a variety of neuronal functions, including synaptic neurotransmitter release, neuronal plasticity, protein phosphorylation, and gene expression. Whereas intracellular calcium concentrations ([Ca²⁺]_i) are precisely regulated through intracellular buffering, binding, and sequestration, alterations in calcium ion homeostasis and influx of Ca²⁺ have been implicated in the pathogenesis of neuronal death and degeneration, as well as cerebral vasospasm associated with multiple types of CNS injury. This review revisits the "calcium hypothesis" of neuronal death associated with traumatic injury to the CNS and examines both the direct and indirect molecular and cellular evidence for calcium-mediated neuropathology, as well as the potential for novel therapeutic strategies targeted at the downstream intracellular effects of calcium signaling and calcium-activated neutral protease (calpain) activation.