Calpastatin, a calpain specific inhibitor, reduce seizures in a mouse model of temporal lobe epilepsy

Epilepsy is a chronic condition characterized by unpredictable and recurrent spontaneous seizures. In a previous study, we reported that pharmacological inhibition of calpain prevented epileptogenesis in the rat pilocarpine model. In this study, we demonstrate that transgenic overexpression of calpastatin, the endogenous inhibitor of calpain, reduces calpain activation and lessens seizure burden in the mouse intrahippocampal kainate model. Blockade of calpain activation was evidenced by a reduction in the generation of spectrin breakdown products, a hallmark of calpain activation. CAST overexpression was associated with a significant reduction in seizure burden, further supporting the idea that blocking calpain overactivation prevents epilepsy. Moreover, a reduction in seizure burden was accompanied by a decrease in inflammatory markers but not cell death. Together, these observations corroborate the role of calpain overactivation in epileptogenesis and provide further support for the use of calpain inhibitors as a viable strategy to prevent epilepsy. PLAIN LANGUAGE SUMMARY: The mechanisms by which brain alterations lead to spontaneous seizures are not well understood. Acquired epilepsy often follows brain trauma. After a brain injury, the activation of the protease calpain has been associated with the development of spontaneous seizures. Our observations indicate that transgenic overexpression of calpastatin, an endogenous inhibitor of calpain, impacts epileptogenesis and reduces seizure burden. This suggests that inhibiting calpain could be a viable strategy to prevent epilepsy.