Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury

• Type of Material: Article
• Authors: Kyria M. Webster, University of Melbourne; David K. Wright, University of Melbourne; Mujun Sun, University of Melbourne; Bridgette D. Semple, University of Melbourne; Ezgi Ozturk, University of Melbourne; Donald Stein, Emory University; Terence J. O’Brien, University of Melbourne; Sandy R. Shultz, University of Melbourne
• Language: English
• Date: 2015-12-18
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © Webster et al. 2015
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12974-015-0457-7
• Title of Journal or Parent Work: Journal of Neuroinflammation
• ISSN: 1742-2094
• Volume: 12
• Issue: 1
• Start Page: 238
• End Page: 238
• Grant/Funding Information: This study was funded by a grant to SRS from the National Health and Medical Research Council (NHMRC #1062653) and fellowships to SRS from the Canadian Institute of Health Research and NHMRC.
• Keywords: ANIMAL-MODEL; MRI; Neurosciences & Neurology; Neurosciences; Astrogliosis; Chronic traumatic encephalopathy; Concussion; Macrophages; LIPID-PEROXIDATION; Immunology; Treatment; COGNITIVE IMPAIRMENT; DTI; Life Sciences & Biomedicine; HIGH-DOSE PROGESTERONE; RECURRENT CONCUSSION; Animal model; Lipid peroxidation; SYNAPTIC PLASTICITY; INFLAMMATORY RESPONSE; Science & Technology; Microglia; FLUID PERCUSSION INJURY; PROFESSIONAL FOOTBALL PLAYERS; BEHAVIORAL IMPAIRMENTS
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience; Health Sciences, Immunology

Abstract

Background: Repeated mild traumatic brain injuries, such as concussions, may result in cumulative brain damage, neurodegeneration and other chronic neurological impairments. There are currently no clinically available treatment options known to prevent these consequences. However, growing evidence implicates neuroinflammation and oxidative stress in the pathogenesis of repetitive mild brain injuries; thus, these may represent potential therapeutic targets. Progesterone has been demonstrated to have potent anti-inflammatory and anti-oxidant properties after brain insult; therefore, here, we examined progesterone treatment in rats given repetitive mild brain injuries via the repeated mild fluid percussion injury model. Methods: Male Long-Evans rats were assigned into four groups: sham injury + vehicle treatment, sham injury + progesterone treatment (8 mg/kg/day), repeated mild fluid percussion injuries + vehicle treatment, and repeated mild fluid percussion injuries + progesterone treatment. Rats were administered a total of three injuries, with each injury separated by 5 days. Treatment was initiated 1 h after the first injury, then administered daily for a total of 15 days. Rats underwent behavioural testing at 12-weeks post-treatment to assess cognition, motor function, anxiety and depression. Brains were then dissected for analysis of markers for neuroinflammation and oxidative stress. Ex vivo MRI was conducted in order to examine structural brain damage and white matter integrity. Results: Repeated mild fluid percussion injuries + progesterone treatment rats showed significantly reduced cognitive and sensorimotor deficits compared to their vehicle-treated counterparts at 12-weeks post-treatment. Progesterone treatment significantly attenuated markers of neuroinflammation and oxidative stress in rats given repeated mild fluid percussion injuries, with concomitant reductions in grey and white matter damage as indicated by MRI. Conclusions: These findings implicate neuroinflammation and oxidative stress in the pathophysiological aftermath of mild brain injuries and suggest that progesterone may be a viable treatment option to mitigate these effects and their detrimental consequences.