title: Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ-1945 in a mouse traumatic brain injury model.
abstract: The efficacy of the amphipathic ketoamide calpain inhibitor SNJ-1945 in attenuating calpain-mediated degradation of the neuronal cytoskeletal protein α-spectrin was examined in the controlled cortical impact (CCI) traumatic brain injury (TBI) model in male CF-1 mice. Using a single early (15 min after CCI-TBI) i.p. bolus administration of SNJ-1945 (6.25, 12.5, 25, or 50-mg/kg), we identified the most effective dose on α-spectrin degradation in the cortical tissue of mice at its 24 h peak after severe CCI-TBI. We then investigated the effects of a pharmacokinetically optimized regimen by examining multiple treatment paradigms that varied in dose and duration of treatment. Finally, using the most effective treatment regimen, the therapeutic window of α-spectrin degradation attenuation was assessed by delaying treatment from 15 min to 1 or 3 h post-injury. The effect of SNJ-1945 on α-spectrin degradation exhibited a U-shaped dose-response curve when treatment was initiated 15 min post-TBI. The most effective 12.5 mg/kg dose of SNJ-1945 significantly reduced α-spectrin degradation by ~60% in cortical tissue. Repeated dosing of SNJ-1945 beginning with a 12.5 mg/kg dose did not achieve a more robust effect compared with a single bolus treatment, and the required treatment initiation was less than 1 h. Although calpain has been firmly established to play a major role in post-traumatic secondary neurodegeneration, these data suggest that even brain and cell-permeable calpain inhibitors, when administered alone, do not show sufficient cytoskeletal protective efficacy or a practical therapeutic window in a mouse model of severe TBI. Such conclusions need to be verified in the human clinical situation.
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Bains
authors.forename: John E
authors.initials: JE
authors.lastname: Cebak
authors.forename: Lesley K
authors.initials: LK
authors.lastname: Gilmer
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Barnes
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Thompson
authors.forename: James W
authors.initials: JW
authors.lastname: Geddes
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors*; D002219:Carbamates / Q000494:pharmacology* / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism
chemical_list: C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; D002219:Carbamates; D013049:Spectrin; D002154:Calpain