Summary Roughly 17,000 people in the United States will suffer a spinal cord injury (SCI) this year. For the vast majority of them, the injury will leave them incapable of walking or, if they have suffered a cervical SCI, entirely dependent upon others for assistance in all of their activities of daily living from feeding to personal care. More importantly, chances of improvement as a result of therapeutic interventions are bleak since there are no approved therapies that enhance functional recovery. The cost to these individuals, and to society as a whole, are significant as SCI often occurs in adults in their peak earning years. Most therapeutic interventions currently being tested are developed for use in the acute period from hours to days after injury. We are developing a small molecule that has neuromodulatory activity for treating both acute and chronic SCI patients. Neuromodulation after injury has the potential to restore functional recovery, as shown by a number of different investigators. After SCI there is an electrochemical imbalance that prevents motor neurons from eliciting normal muscle actions that are critical for movement of arms and legs. This imbalance is partly caused by a decrease in the chloride transporter called KCC2. It has been shown that by restoring normal levels of this transporter in spared spinal cord neurons, paralyzed mice regain walking ability. This grant application aims to examine new compounds that have the potency and properties to be translated towards human clinical studies, by testing them in preclinical models.