Spinal cord injury (SCI) evokes an increase in intracellular free Ca(2+) level resulting in activation of
calpain, a Ca(2+)-dependent
cysteine protease, which cleaves many cytoskeletal and
myelin proteins.
Calpain is widely expressed in the central nervous system (CNS) and regulated by
calpastatin, an endogenous
calpain-specific inhibitor.
Calpastatin degraded by overactivation of
calpain after SCI may lose its regulatory efficiency. Evidence accumulated over the years indicates that uncontrolled
calpain activity mediates the degradation of many cytoskeletal and
membrane proteins in the course of neuronal death and contributes to the pathophysiology of SCI. Cleavage of the key cytoskeletal and
membrane proteins by
calpain is an irreversible process that perturbs the integrity and stability of CNS cells leading to cell death.
Calpain in conjunction with
caspases, most notably
caspase-3, can cause apoptosis of the CNS cells following
trauma. Aberrant Ca(2+) homeostasis following SCI inevitably activates
calpain, which has been shown to play a crucial role in the pathophysiology of SCI. Therefore,
calpain appears to be a potential therapeutic target in SCI. Substantial research effort has been focused upon the development of highly specific inhibitors of
calpain and
caspase-3 for therapeutic applications. Administration of cell permeable and specific inhibitors of
calpain and
caspase-3 in experimental animal models of SCI has provided significant neuroprotection, raising the hope that humans suffering from SCI may be treated with these inhibitors in the near future.