Traumatic Brain Injury (TBI) is a significant public health problem in the United States. In 2013 alone, an estimated 2.8 million TBI cases presented for treatment and it is likely that many more cases were never reported (https://www.cdc.gov/traumaticbraininjury/get_the_facts.html). In recent years, repeated mild traumatic brain injury has received a lot of attention, after it was found that many military veterans and athletes subjected to repeated concussions exhibit a chronic degenerative disease referred to as Chronic Traumatic Encephalopathy (CTE).  TBI causes significant neuronal degeneration and currently, there are no treatments targeting neuronal death after TBI. We have identified a molecular mechanism that is activated in the hours following TBI, lasts for several days and is directly related to neuronal degeneration. This mechanism consists in the prolonged activation of the calcium-dependent protease, calpain-2. An inhibitor of this mechanism (referred to as C2I) provides significant protection against neurodegeneration and improves recovery of motor and cognitive functions in a mouse model of TBI, and significantly decreases the levels of a blood biomarker correlated with the long-term negative consequences of TBI. A lead clinical candidate, NA184, has been selected to be moved to clinical trials.