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 phos phorylation, and gene expression. Whereas intracellular calcium concentrations ([Ca2+]i) are precisely reg ulated through intracellular buffering, binding, and sequestration, alterations in calcium ion homeostasis and influx of Ca 2+ 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 hypoth esis" 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. NEUROSCIENTIST 3:169-175, 1997
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