TY - JOUR
T1 - Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ-1945 in a mouse traumatic brain injury model
AU - Bains, Mona
AU - Cebak, John E.
AU - Gilmer, Lesley K.
AU - Barnes, Colleen C.
AU - Thompson, Stephanie N.
AU - Geddes, James W.
AU - Hall, Edward D.
AU - Markesbery, William R.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - SNJ-1945
KW - calpain
KW - neuroprotection
KW - traumatic brain injury
KW - α-spectrin
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U2 - 10.1111/jnc.12118
DO - 10.1111/jnc.12118
M3 - Article
C2 - 23216523
AN - SCOPUS:84875242230
SN - 0022-3042
VL - 125
SP - 125
EP - 132
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 1
ER -