Acute neuropathology following experimental
traumatic brain injury results in the rapid
necrosis of cortical tissue at the site of injury. This primary injury is exacerbated in the ensuing hours and days via the progression of secondary injury mechanism(s) leading to significant neurological dysfunction. Recent evidence from our laboratory demonstrates that the
immunosuppressant cyclosporin A significantly ameliorates cortical damage following
traumatic brain injury. The present study extends the previous findings utilizing a unilateral controlled cortical impact model of
traumatic brain injury in order to establish a dose-response curve and optimal dosing regimen of
cyclosporin A. Following injury to adult rats,
cyclosporin A was administrated at various dosages and the
therapy was initiated at different times post-injury. In addition to examining the effect of
cyclosporin A on the acute disruption of the blood-brain barrier following controlled cortical impact, we also assessed the efficacy of
cyclosporin A to reduce tissue damage utilizing the fluid percussion model of
traumatic brain injury. The findings demonstrate that the neuroprotection afforded by
cyclosporin A is dose-dependent and that a therapeutic window exists up to 24h post-injury. Furthermore, the optimal
cyclosporin dosage and regimen markedly reduces disruption of the blood-brain barrier acutely following a
cortical contusion injury, and similarly affords significant neuroprotection following fluid percussion injury. These findings clearly suggest that the mechanisms responsible for tissue
necrosis following
traumatic brain injury are amenable to pharmacological intervention.