Investigation of Novel CYP26 Inhibitor for Treatment of Traumatic Brain Injury

Over 5.4 million Americans are living with traumatic brain injury (TBI) related symptoms today, with 10 million occurring annually on a global level. While once considered an isolated event, current research is redefining TBIs as the initiation of a disease process that can last a lifetime and impact multiple organ systems. Within the nervous system, injury occurs in two phases: the initial insult, and a post-traumatic inflammatory response. Retinoic acid (RA) signal transduction is activated when contusions, compressions, and lacerations occur in the nervous system, and recent studies have shown that endogenous RA in the brain supports neuronal protection, axonal growth, inflammatory signal modulation, and glial differentiation. RA biosynthesis is a highly regulated pathway where metabolism is controlled by retinoic acid hydroxylases, CYP26. Thus, inhibition of CYP26 is a promising mechanism to increase endogenous RA and promote healing from TBI. We hypothesize that inhibition of CYP26 with synthetic compounds will reduce TBI pathology through the modulation of neurotrophic and anti-inflammatory factors. To test this, in vivo experiments were performed with a small molecule CYP26 inhibitor, DX308. We found that DX308 significantly reduces TBI behavioral symptoms in rodent TBI models, including protection from paretic circling. Additionally, limb placement and sensory motor function significantly recover in the three days following treatment, suggestive of reduced inflammation and wound healing with DX308 treatment. Collectively, these studies suggest that CYP26 inhibition may rescue TBI pathology through increased levels of endogenous RA