Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ-1945 in a mouse traumatic brain injury model

Mona Bains, John E. Cebak, Lesley K. Gilmer, Colleen C. Barnes, Stephanie N. Thompson, James W. Geddes, Edward D. Hall, William R. Markesbery

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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. This study details a dose-response and therapeutic window analysis of the brain and cell penetrable calpain inhibitor SNJ-1945 concerning its ability to reduce cortical cytoskeletal degradation when administered during the first minutes and hours after controlled cortical impact traumatic brain injury in the mouse. The compound produced a maximum 60% decrease in cytoskeletal damage when administered within the first hour after TBI, but lost its effect if treatment was delayed for 1 hour. These results fail to support the clinical practicality of direct calpain inhibition as a neuroprotective strategy.

Original languageEnglish
Pages (from-to)125-132
Number of pages8
JournalJournal of Neurochemistry
Issue number1
StatePublished - Apr 2013


  • SNJ-1945
  • calpain
  • neuroprotection
  • traumatic brain injury
  • α-spectrin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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