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 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.
Sullivan
P G
PG
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Rabchevsky
A G
AG
Hicks
R R
RR
Gibson
T R
TR
Fletcher-Turner
A
A
Scheff
S W
SW
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D016572:Cyclosporine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010474:Percussion / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D016572:Cyclosporine