Targeting Mitochondrial Dysfunction to Promote Functional Neuroprotection After Spinal Cord Injury

Over 12,000 new cases of SCI occur in the United States of America every year. The resulting cost of care is estimated at greater than $3 million per patient, placing tremendous burdens on not only patient caregivers, but also the healthcare system in general. There are no FDA-approved therapeutics to promote recovery after spinal cord injury (SCI). As such, therapeutics are desperately needed to treat acute SCI. Mitochondrial dysfunction is fundamental to neuropathological sequelae following traumatic SCI. Our research group has documented that pharmacologically sustaining mitochondrial bioenergetics at early stages following contusion SCI results in long-term functional neuroprotection. The current proposal is built upon the idea that modulating mitochondrial physiology using mild mitochondrial uncoupling will increase proton flux across the inner mitochondrial membrane, thereby lowering mitochondrial membrane potential (ΔΨm) and reducing oxidative stress. The fine line between cell survival and cell death relies on mitochondrial integrity, and ultimately the state of ΔΨm. Accordingly, we have documented that mild uncoupling with DNP significantly improves mitochondrial bioenergetics and reduces oxidative stress following contusion SCI. Our collaborators have further reported that mild uncoupling with DNP and carbonyl cyanide-4-phenylhydrazone (FCCP) is neuroprotective in rodent models of traumatic brain injury (TBI). With growing evidence in our research group that mild uncoupling produces neuroprotective effects following neurotrauma, we now seek to explore whether MP201, a prodrug of DNP with a greatly reduced maximum concentration (Cmax) and longer residence time, can maintain metabolic integrity and foster long-term behavioral improvements after contusion SCI in rats. Use of uncouplers is a biophysics approach and not a classic pharmacology approach which is novel in many ways and puts MP201 in the class that has not been tested. Using a contusion SCI model in adult rats, in Aim 1, will establish optimal dosage and therapeutic time window of MP201 treatment for mitochondrial bioenergetic improvement following acute contusion SCI. Aim 2 will determine whether the optimal acute dosage regimen of MP201 promotes long-term functional neuroprotection following contusion SCI.