title: Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress.
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.
authors.affiliation: Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Kaori H
authors.initials: KH
authors.lastname: Yamada
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Kozlowski
authors.forename: Stacey E
authors.initials: SE
authors.lastname: Seidl
authors.forename: Steven
authors.initials: S
authors.lastname: Lance
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Wieschhaus
authors.forename: Premanand
authors.initials: P
authors.lastname: Sundivakkam
authors.forename: Chinnaswamy
authors.initials: C
authors.lastname: Tiruppathi
authors.forename: Imran
authors.initials: I
authors.lastname: Chishti
authors.forename: Ira M
authors.initials: IM
authors.lastname: Herman
authors.forename: Shafi M
authors.initials: SM
authors.lastname: Kuchay
authors.forename: Athar H
authors.initials: AH
authors.lastname: Chishti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000235:genetics* / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D051033:Apoptosis Inducing Factor; C494830:AIFM1 protein, mouse; D034741:RNA, Small Interfering; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3; C112682:Capn1 protein, mouse; D002118:Calcium