Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats

Acute neuropathology following experimental traumatic brain injury results in the rapid necrosis of cortical tissue at the site of injury. This primar y injury is exacerbated in the ensuing hours and days via the progression o f secondary injury mechanism(s) leading to significant neurological dysfunc tion, Recent evidence from our laboratory demonstrates that the immunosuppr essant cyclosporin A significantly ameliorates cortical damage following tr aumatic brain injury. The present study extends the previous findings utili zing a unilateral controlled cortical impact model of traumatic brain injur y in order to establish a dose-response curve and optimal dosing regimen of cyclosporin A. Following injury to adult rats, cyclosporin A was administr ated at various dosages and the therapy was initiated at different times po st-injury. In addition to examining the effect of cyclosporin A on the acut e disruption of the blued-brain barrier following controlled cortical impac t, we also assessed the efficacy of cyclosporin A to reduce tissue damage u tilizing 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 24 h post-inj ury. Furthermore, the optimal cyclosporin dosage and regimen markedly reduc es disruption of the blood-brain barrier acutely following a cortical contu sion injury, and similarly affords significant neuroprotection following fl uid percussion injury. These findings clearly suggest that the mechanisms r esponsible for tissue necrosis following traumatic brain injury are amenabl e to pharmacological intervention. (C) 2000 IBRO. Published by Elsevier Sci ence Ltd. All rights reserved.