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 tiss ue at the site of injury. In the ensuing hours and days, secondary injury e xacerbates the original damage resulting in significant neurological dysfun ction. Recent reports from our lab demonstrate that a bolus injection of th e immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. C sA transiently inhibits the opening of the mitochondrial permeability trans ition 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 d eformation and the extent of cortical damage was assessed using modern ster eological techniques. Animals were administrated a 20 mg/kg intraperitoneal bolus of CsA or vehicle 15 min postinjury and osmotic minipumps were impla nted subcutaneously to deliver CsA (4.5 or 10 mg/kg/day) or vehicle. All an imals receiving CsA demonstrated a significant reduction in lesion volume, with the highest dose offering the most neuroprotection (74% reduction in l esion volume). These results extend our previous findings and demonstrate t hat chronic infusion of CsA is neuroprotective following TBI. These finding s also suggest that the mechanisms responsible for tissue necrosis followin g TBI are amenable to manipulation. (C) 2000 Academic Press.