Mitochondrial dysfunction is known to play a pivotal role in cell death mechanisms following
traumatic brain injury (TBI). N-methyl-4-isoleucine-cyclosporin (
NIM811), a non-immunosuppressive
cyclosporin A (CsA) analog, inhibits the
mitochondrial permeability transition pore (mPTP) and has been shown to be neuroprotective following TBI in mice. However, the translation of the
neuroprotective effects of
mPTP inhibitors, including CsA and
NIM811, into improved cognitive end points has yet to be fully investigated. Therefore, to build upon these results, a severe unilateral controlled cortical impact model of TBI was used in the present study to establish a dose-response curve for
NIM811 in rats. The findings demonstrate that the neuroprotection afforded by
NIM811 is dose dependent, with the 10 mg/kg dose being the most effective dose. Once the dose response was established, we evaluated the effect of the optimal dose of
NIM811 on behavior, mitochondrial bioenergetics, and mitochondrial oxidative damage following TBI. For behavioral studies, rats were administered
NIM811 at 15 min and 24 h post-injury, with cognitive testing beginning 10 days post-injury. Mitochondrial studies involved a single injection of
NIM811 at 15 min post-injury followed by mitochondrial isolation at 6 h post-injury. The results revealed that the optimal dose of
NIM811 improves cognition, improves mitochondrial functioning, and reduces oxidative damage following TBI.