A M. CHOO, R KOMLO, M MANZANO, A BARBOSA, Q CHANG, T HANANIA
Progesterone was previously reported to improve outcomes in preclinical studies of traumatic brain injury. Recent phase 3 clinical trials, however, reported no clinical benefit of progesterone treatment for moderate-to-severe as well as severe traumatic brain injuries. Given the heterogeneity in human traumatic brain injuries, we aimed to reassess the effectiveness of progesterone treatment in two preclinical traumatic brain injury models. We compared progesterone treatment (16 mg/kg for 5 days) in mechanically identical controlled cortical impacts to the medial frontal cortex and the parasagittal cortex in rats. During the first week following injury, progesterone improved motor performance on the beam balance in both injury models. In the Morris water maze test, progesterone improved learning and memory only in animals that had received impacts to the medial frontal cortex and not in the parasagittal injury model. In the elevated plus maze, lesions to the medial frontal cortex increased the time the rats spent in the open arms which may indicate decreased anxiety and greater risk-taking behavior. This behavior was not attenuated by progesterone. The increase in the open arm time was modest in parasagittal injuries. Nonetheless, progesterone attenuated this modest increase back to levels similar to that of sham surgical controls. These data illustrate that the efficacy of post-traumatic progesterone treatment may depend on the brain region injured. Hence, the clinical translation of progesterone could benefit from additional stratification of patients accounting for the position of the brain lesions.