• P G Sullivan, M B Thompson, and S W Scheff.
• Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
• Exp. Neurol. 1999 Nov 1;160(1):226-34.

AbstractExperimental traumatic brain injury (TBI) results in a rapid and significant necrosis of cortical tissue at the site of injury. In the ensuring hours and days, secondary injury exacerbates the primary damage, resulting in significant neurological dysfunction. Recent reports from our lab and others have demonstrated that the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. The opening of the mitochondrial permeability transition pore (MPTP) is inhibited by CsA, thereby maintaining the mitochondrial membrane potential and calcium homeostasis in isolated mitochondrial. In the present study we utilized a unilateral controlled cortical impact model of TBI to assess mitochondrial dysfunction in both isolated mitochondria and synaptosomes to elucidate the neuroprotective role of CsA. The results demonstrate that administration of CsA 15 min postinjury significantly attenuates mitochondrial dysfunction as measured using several biochemical assays of mitochondria integrity and energetics. Following TBI, mitochondria isolated from the injured cortex of animals treated with CsA demonstrate a significant increase in mitochondria membrane potential and are resistant to the induction of mitochondrial permeability transition compared to vehicle-treated animals. Similarly, synaptosomes isolated from CsA-treated animals demonstrate a significant increase in mitochondria membrane potential, accompanied by lower levels of intramitochondrial Ca2+ and reactive oxygen species production than seen in vehicle-treated animals. These results suggest that the neuroprotective properties of CsA are mediated through modulation of the MPTP and maintenance of mitochondria homeostasis. Amelioration of cortical damage with CsA indicates that pharmacological therapies can be devised which will significantly alter neurological outcome after injury.

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