Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury

Abstract

Objective: Inflammation is an important component of the response to traumatic brain injury (TBI). Progesterone has been shown to inhibit neuroinflammation following (TBI) and may do so through Toll-like receptor (TLR)-mediated pathways. In vitro studies indicate that 1,25-dihydroxyvitamin D(3) (VDH) may also modulate the inflammatory response through the TLR4 pathway. This study tested the hypothesis that PROG and VDH would exert additive and synergistic neuroprotective effects compared with individual treatment by modulating TLR4/NF-κB-mediated inflammation pathways after TBI in rats.

Research design and methods: Bilateral medial frontal cortical impact injury was induced in young adult Sprague-Dawley rats. Progesterone (i.p., 16 mg kg⁻¹ body weight) and VDH (1 µg kg⁻¹ body weight) were injected separately or combined at 1 and 6 hours after surgery. Rats were killed 24 hours post-surgery and peri-contusional brain tissue harvested for immunostaining and protein measurement.

Results: TLR4, phosphorylation of NF-κB, neuronal loss and astrocyte activation were significantly reduced with combination treatment after TBI compared to each agent given individually.

Conclusions: At 24 hours after TBI, combination therapy shows greater efficacy in reducing neuroinflammation compared to progesterone and VDH given separately, and does so by modulating the TLR4/NF-κB signalling pathway.

• Cytokines
• frontal cortex
• neurosteroids
• neuroprotection
• toll-like receptors

Acknowledgments

The authors would like to thank Leslie McCann for invaluable editorial assistance and Jason S. Lee for his assistance with immunostaining for this project.

Declaration of interest

The research reported in the paper was supported by NIH 5 R01 HD61971 and by gifts from BHR Pharma, The Marcus Foundation, and Allen and Company. The authors report no conflicts of interest.