Combinatorial treatment with progesterone and thyrotropin releasing hormone improves outcomes after traumatic brain injury

Previous work has shown that the neurosteroid progesterone (PROG) and hypothalamic hormone thyrotropin releasing hormone (TRH) improve molecular and functional outcomes following traumatic brain injury (TBI) when used independently. This work was designed to evaluate if a combination of PROG and TRH results in further improvements in outcomes. Adult male Sprague‐Dawley rats were given a medial frontal cortex contusion using a weight‐drop device after craniotomy. After TBI, rats were treated with PROG (5 d), TRH (1 injection at 1 h post‐injury), or the combination of the two drugs (PROG+TRH). Uninjured sham‐operated and vehicle‐treated TBI rats served as controls. PROG+TRH treatment resulted in significant improvements in both sensory skills and learning and memory as measured by the tactile adhesive test and Morris Water Maze, respectively (n=11/group). Analysis of putative mechanisms responsible for these behavioral observations suggest that the tumor suppressor protein p53, the inflammatory marker TNF‐α, and GFAP‐positive reactive gliosis may all participate in the efficacy of this combinatorial treatment. Furthermore, preliminary use of diffusion magnetic resonance imaging at 21 Tesla (21T) suggests that diffusion MRI is a valuable novel tool in future determination of mechanisms and the ways to reduce water accumulation and edema after treatment.