Vitamin D improves progesterone‐mediated reductions in edema following traumatic brain injury

Edema and intracranial pressure associated with traumatic brain injury (TBI) result in poor long‐term clinical outcomes. Thus, we need to improve our understanding of the mechanisms that result in edema and develop new treatments to target water accumulation. Progesterone (PROG) has been shown to reduce edema after TBI. Because 1, 25 dihydroxyvitamin D (D) and PROG both interact with nuclear RXR receptors to regulate gene expression, we hypothesized that acute treatments with the active form of vitamin D could be a useful adjunct to progesterone treatment. TBI was introduced by weight‐drop (300g) creating a 2mm medial frontal cortex contusion following craniotomy in male Fisher rats. Animals were then treated at 1 and 6 hrs post‐injury with vehicle, PROG (16mg/kg), D (2.5 µg/kg), or PROG+D. At 24 h, direct measurements of water accumulation around the site of injury showed that while D alone was ineffective, there was a 4% reduction in water accumulation in PROG treated rats, and a 9% reduction in PROG+D animals. Edema results from vasogenic water accumulation after blood‐brain‐barrier damage and cytotoxic water from cell damage. Water regulating protein aquaporin‐4 was not changed after treatment. Novel in vivo diffusion magnetic resonance imaging at 21 Tesla (21T) allowed us to visualize and distinguish vasogenic and cytotoxic edema. MRI results support that PROG +D protects against vasogenic and cytotoxic edema.