Traumatic brain injury (TBI) results in abrupt, initial cell damage leading to delayed neuronal death. The
calcium-activated
proteases, calpains, are known to contribute to this secondary neurodegenerative cascade. Although the specific inhibitor of calpains,
calpastatin, is present within neurons, normal levels of
calpastatin are unable to fully prevent the damaging proteolytic activity of calpains after injury. In this study, increased
calpastatin expression was achieved using transgenic mice that overexpress the human
calpastatin (hCAST) construct under control of a
calcium-
calmodulin-dependent
kinase II α promoter. Naïve hCAST transgenic mice exhibited enhanced neuronal
calpastatin expression and significantly reduced
protease activity. Acute
calpain-mediated
spectrin proteolysis in the cortex and hippocampus induced by controlled cortical impact
brain injury was significantly attenuated in
calpastatin overexpressing mice. Aspects of posttraumatic motor and cognitive behavioral deficits were also lessened in hCAST transgenic mice compared to their wildtype littermates. However, volumetric analyses of neocortical
contusion revealed no histological neuroprotection at either acute or long-term time points. Partial hippocampal neuroprotection observed at a moderate injury severity was lost after severe TBI. This study underscores the effectiveness of
calpastatin overexpression in reducing
calpain-mediated proteolysis and behavioral impairment after TBI, supporting the therapeutic potential for
calpain inhibition. In addition, the reduction in
spectrin proteolysis without accompanied neocortical neuroprotection suggests the involvement of other factors that are critical for neuronal survival after
contusion brain injury.