Voltage-Gated Calcium Channel Blockers for the Treatment of Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, and, to date, no pharmacological agents are known to improve neurological outcome following injury. TBI is associated with a severity-dependent accumulation of intracellular calcium ([Ca²⁺]_i) lasting hours-to-days postinjury and driving apoptotic and necrotic cell death. Pathological accumulation of calcium can also lead to breakdown of structural proteins and changes in gene expression resulting in long-term dysfunction of surviving cells. In in vitro models of TBI, L- and N-type voltage-gated calcium channel (VGCC) blockers reduced [Ca²⁺]_i accumulation and glutamate release resulting in reduced cell death. In rodent models of TBI, administration of VGCC blockers reduced cell death and improved spatial learning and motor function. Based on these data, there is a clear role of VGCC in postinjury pathophysiology, and manipulation of these channels has the potential to improve neurological outcome following injury.