Cell Cycle Inhibition Reduces Inflammatory Responses, Neuronal Loss, and Cognitive Deficits Induced by Hypobaria Exposure Following Traumatic Brain Injury
Journal Article - Open Access
USAFSAM/FHE Wright-Patterson AFB United States
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Traumatic brain injury TBI patients in military settings can be exposed to prolonged periods of hypobaria HB during aeromedicalevacuation. Hypobaric exposure, even with supplemental oxygen to prevent hypoxia, worsens outcome after experimental TBI, in partby increasing neuroinflammation. Cell cycle activation CCA after TBI has been implicated as a mechanism contributing to bothpost-traumatic cell death and neuroinflammation. Here, we examined whether hypobaric exposure in rats subjected to TBI increasesCCA and microglial activation in the brain, as compared to TBI alone, and to evaluate the ability of a cyclin-dependent kinase CDKinhibitor CR8 to reduce such changes and improve behavioral outcomes. Adult male Sprague Dawley rats were subjected to fluidpercussion-induced injury, and HB exposure was performed at 6 h after TBI. Western blot and immunohistochemistry IHC wereused to assess cell cycle-related protein expression and inflammation at 1 and 30 days after injury. CR8 was administeredintraperitoneally at 3 h post-injury chronic functional recovery and histological changes were assessed. Post-traumatic hypobaricexposure increased upregulation of cell cycle-related proteins cyclin D1, proliferating cell nuclear antigen, and CDK4 andmicroglialmacrophage activation in the ipsilateral cortex at day 1 post-injury as compared to TBI alone. Increased immunoreactivityof cell cycle proteins, as well as numbers of Iba-1 and GFAP cells in both the ipsilateral cortex and hippocampus were found at day30 post-injury. TBIHB significantly increased the numbers of NADPH oxidase 2 gp91phox enzyme-expressing cells that were co-localizedwith Iba-1. Each of these changes was significantly reduced by the administration of CR8.
- Medicine and Medical Research
- Anatomy and Physiology