Cyclosporin A attenuates acute mitochondrial dysfunction following traumatic brain injury

Experimental traumatic brain injury (TBI) results in a rapid and significan t necrosis of cortical tissue at the site of injury. In the ensuring hours and days, secondary injury exacerbates the primary damage, resulting in sig nificant neurological dysfunction. Recent reports from our lab and others h ave demonstrated that the immunosuppressant cyclosporin A (CsA) is neuropro tective following TBI. The opening of the mitochondrial permeability transi tion pore (MPTP) is inhibited by CsA, thereby maintaining the mitochondrial membrane potential and calcium homeostasis in isolated mitochondrial. In t he present study we utilized a unilateral controlled cortical impact model of TBI to assess mitochondrial dysfunction in both isolated mitochondria an d synaptosomes to elucidate the neuroprotective role of CsA. The results de monstrate that administration of CsA 15 min postinjury significantly attenu ates mitochondrial dysfunction as measured using several biochemical; assay s of mitochondria integrity and energetics Following TBI, mitochondria isol ated from the injured cortex of animals treated with CsA demonstrate a sign ificant increase in mitochondria membrane potential and are resistant to th e induction of mitochondrial permeability transition compared to vehicle-tr eated animals. Similarly, synaptosomes isolated from CsA-treated animals de monstrate a significant increase in mitochondria membrane potential, accomp anied by lower levels of intramitochondrial Ca2+ and reactive oxygen specie s production than seen in vehicle-treated animals. These results suggest th at, the neuroprotective properties of CsA are mediated through modulation o f the MPTP and maintenance of mitochondria homeostasis, Amelioration of cor tical damage with CsA indicates that pharmacological therapies can be devis ed which will significantly alter neurological outcome after injury. (C) 19 99 Academic Press.