¹Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA

Correspondence: Dr ED Hall, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, 741 South Limestone Street, Room B483 BBSRB, Lexington, KY 40536, USA. E-mail: edhall@uky.edu

Received 29 May 2008; Revised 23 July 2008; Accepted 23 July 2008; Published online 20 August 2008.

Abstract

Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (-spectrin) degradation, neurodegeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated -spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased -spectrin breakdown products observed in vehicle-treated animals (P<0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days (P<0.005) and neurodegeneration at 7 days postinjury (P<0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce -spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA.