Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury.
Traumatic brain injury (TBI) results in the rapid necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage resulting in significant neurological dysfunction. Recent reports from our lab demonstrate that a bolus injection of the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. CsA transiently inhibits the opening of the mitochondrial permeability transition pore and maintains calcium homeostasis in isolated mitochondria. The present study utilized a unilateral controlled cortical impact model of TBI to assess whether the neuroprotective effects of CsA could be extended by chronic infusion. Adult rats were subjected to a moderate (2 mm) cortical deformation and the extent of cortical damage was assessed using modern stereological techniques. Animals were administrated a 20 mg/kg intraperitoneal bolus of CsA or vehicle 15 min postinjury and osmotic minipumps were implanted subcutaneously to deliver CsA (4.5 or 10 mg/kg/day) or vehicle. All animals receiving CsA demonstrated a significant reduction in lesion volume, with the highest dose offering the most neuroprotection (74% reduction in lesion volume). These results extend our previous findings and demonstrate that chronic infusion of CsA is neuroprotective following TBI. These findings also suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation.
Sullivan
P G
PG
Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, 40536-0230, USA.
Thompson
M
M
Scheff
S W
SW
D000818:Animals; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D018696:Neuroprotective Agents; D016572:Cyclosporine