Abstract
Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways. Here, we used our calpain-1 null mouse model to evaluate the function of calpain-1 in neural degeneration following a rodent model of traumatic brain injury. In vivo, calpain-1 null mice show significantly less neural degeneration and apoptosis and a smaller contusion 3 days post-injury than wild type littermates. Protection from traumatic brain injury corroborated with the resistance of calpain-1 neurons to apoptosis induced by oxidative stress. Biochemical analysis revealed that caspase-3 activation, extracellular calcium entry, mitochondrial membrane permeability, and release of apoptosis-inducing factor from mitochondria are partially blocked in the calpain-1 null neurons. These findings suggest that the calpain-1 knock-out mice may serve as a useful model system for neuronal protection and apoptosis in traumatic brain injury and other neurodegenerative disorders in which oxidative stress plays a role.
Highlights
Calpains play an important role in the regulation of cell death
We investigated the function of calpain-1 in neurodegeneration induced by traumatic brain injury (TBI) and neuronal apoptosis induced by oxidative stress
These findings indicate that calpain-1 plays a significant role in the induction of neural degeneration and apoptosis following TBI
Summary
Calpains play an important role in the regulation of cell death. Results: Calpain-1 inhibition decreases cortical neurodegeneration following TBI by regulating calcium influx and apoptosis of neurons under oxidative stress. Biochemical analysis revealed that caspase-3 activation, extracellular calcium entry, mitochondrial membrane permeability, and release of apoptosis-inducing factor from mitochondria are partially blocked in the calpain-1 null neurons These findings suggest that the calpain-1 knock-out mice may serve as a useful model system for neuronal protection and apoptosis in traumatic brain injury and other neurodegenerative disorders in which oxidative stress plays a role. Our in vitro studies demonstrate the potential molecular mechanism of calpain-1 in apoptosis and show that it plays a functional role in the regulation of extracellular calcium influx and apoptosis in primary neurons exposed to oxidative stress Together, these findings reveal a physiological role of calpain-1 in the regulation of calcium influx and apoptosis of primary neurons subjected to oxidative stress and in neuronal death following traumatic brain injury
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