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: Mona Bains, John E Cebak, Lesley K Gilmer, Colleen C Barnes, Stephanie N Thompson, James W Geddes, Edward D Hall
• Journal: Journal of neurochemistry (J Neurochem) Vol. 125 Issue 1 Pg. 125-32 (Apr 2013) ISSN: 1471-4159 [Electronic] England
• PMID: 23216523 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 International Society for Neurochemistry.

Chemical References

• ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester
• Carbamates
• Spectrin
• Calpain

Topics

• Animals
• Brain Injuries (drug therapy, metabolism, pathology)
• Calpain (antagonists & inhibitors)
• Carbamates (pharmacology, therapeutic use)
• Cerebral Cortex (drug effects, metabolism, pathology)
• Cytoskeleton (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Male
• Mice
• Neurons (drug effects, metabolism)
• Spectrin (metabolism)