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

Authors

  • Mona Bains,

    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    Search for more papers by this author
  • John E. Cebak,

    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    Search for more papers by this author
  • Lesley K. Gilmer,

    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    Search for more papers by this author
  • Colleen C. Barnes,

    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    Search for more papers by this author
  • Stephanie N. Thompson,

    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    Search for more papers by this author
  • James W. Geddes,

    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    Search for more papers by this author
  • Edward D. Hall

    Corresponding author
    1. Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
    • Address correspondence and reprint requests to Edward D. Hall, PhD, William R. Markesbery, M.D. Chair in Neurotrauma Research, Spinal Cord & Brain Injury Research Center (SCoBIRC), Professor, Anatomy & Neurobiology, Neurosurgery, Neurology and Physical Medicine & Rehabilitation, University of Kentucky Medical Center, Room B477, Biomedical & Biological Sciences Research Building, 741 S. Limestone Street, Lexington, KY 40536-0509, USA. E-mail: edhall@uky.edu

    Search for more papers by this author

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.

Ancillary