title: A calpain inhibitor ameliorates seizure burden in an experimental model of temporal lobe epilepsy.
abstract: In this study, we used the pilocarpine model of epilepsy to evaluate the involvement of calpain dysregulation on epileptogenesis. Detection of spectrin breakdown products (SBDPs, a hallmark of calpain activation) after induction of pilocarpine-induced status epilepticus (SE) and before appearance of spontaneous seizure suggested the existence of sustained calpain activation during epileptogenesis. Acute treatment with a cell permeable inhibitor of calpain, MDL-28170, resulted in a partial but significant reduction on seizure burden. The reduction on seizure burden was associated with a limited reduction on the generation of SBDPs but was correlated with a reduction in astrocytosis, microglia activation and cell sprouting. Together, these observations provide evidence for the role of calpain in epileptogenesis. In addition, provide proof-of-principle for the use of calpain inhibitors as a novel strategy to prevent epileptic seizures and its associated pathologies.
authors.affiliation: Department of Pediatrics, Division of Neurology and Translational Epilepsy Research Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Lam
authors.affiliation: Department of Pediatrics, Division of Neurology and Translational Epilepsy Research Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Pediatrics, Division of Neurology and Translational Epilepsy Research Program, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: marco.gonzalez@ucdenver.edu.
authors.forename: Marco I
authors.initials: MI
authors.lastname: González
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002154:Calpain / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010862:Pilocarpine; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000927:Anticonvulsants; D004151:Dipeptides; D006023:Glycoproteins; C039304:calpain inhibitors; D010862:Pilocarpine; D002154:Calpain; C058076:calpain inhibitor III
keywords: Calpain; Epilepsy; Epileptogenesis; Proteolysis; Spontaneous seizures