Post-Injury Treatment with NIM811 Promotes Recovery of Function in Adult Female Rats after Spinal Cord Contusion: A Dose-Response Study

Mitochondrial homeostasis is essential for maintaining cellular function and survival in the central nervous system (CNS). Mitochondrial function is significantly compromised after spinal cord injury (SCI) and is associated with accumulation of high levels of calcium, increased production of free radicals, oxidative damage, and eventually mitochondrial permeability transition (mPT). The formation of the mPT pore (mPTP) and subsequent mPT state are considered to be end stage events in the decline of mitochondrial integrity, and strategies that inhibit mPT can limit mitochondrial demise. Cyclosporine A (CsA) is thought to inhibit mPT by binding to cyclophilin D and has been shown to be effective in models of CNS injury. CsA, however, also inhibits calcineurin, which is responsible for its immunosuppressive properties. In the present study, we conducted a dose-response examination of NIM811, a nonimmunosuppressive CsA analog, on recovery of function and tissue sparing in a rat model of moderate to severe SCI. The results of our experiments revealed that NIM811 (10 mg/kg) significantly improved open field locomotor performance, while the two higher doses tested (20 and 40 mg/kg) significantly improved return of reflexive bladder control and significantly decreased the rostral-caudal extent of the lesion. Taken together, these results demonstrate the ability of NIM811 to improve recovery of function in SCI and support the role of protecting mitochondrial function as a potential therapeutic target.