The cytoskeletal and neuronal protective effects of early treatment with the blood-brain barrier- and cell-permeable
calpain inhibitor MDL-28170 was examined in the controlled cortical impact (CCI)
traumatic brain injury (TBI) model in male CF-1 mice. This was preceded by a dose-response and pharmacodynamic evaluation of IV or IP doses of
MDL-28170 with regard to ex vivo inhibition of
calpain 2 activity in harvested brain homogenates. From these data, we tested the effects of an optimized
MDL-28170 dosing regimen on
calpain-mediated degradation of the neuronal cytoskeletal
protein α-
spectrin in cortical or hippocampal tissue of mice 24 h after CCI-TBI (1.0 mm depth, 3.5 m/sec velocity). With treatment initiated at 15 min post-TBI, α-
spectrin degradation was significantly reduced by 40% in hippocampus and 44% in cortex. This effect was still observed with a 1-h but not a 3-h post-TBI delay. The cytoskeletal protection is most likely taking place in neurons surrounding the area of mainly necrotic degeneration, since
MDL-28170 did not reduce hemispheric lesion volume as measured by the aminocupric
silver staining method. This lack of effect on lesion volume has been seen with other
calpain inhibitors, which suggests that pharmacological
calpain inhibition by itself, while able to reduce axonal injury, may not be able to produce a measurable reduction in lesion volume. This is in contrast to certain other neuroprotective mechanistic approaches such as the mitochondrial protectant
cyclosporine A, which produces at least a partial decrease in lesion volume in the same model. Accordingly, the combination of a
calpain inhibitor with a compound such as
cyclosporine A may be needed to achieve the optimal degree of post-TBI neuroprotection.