title: Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury.
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.
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Kyria M
authors.initials: KM
authors.lastname: Webster
authors.affiliation: Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, 3010, Australia.|The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Wright
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Mujun
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Bridgette D
authors.initials: BD
authors.lastname: Semple
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Ozturk
authors.affiliation: Department of Emergency Medicine, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia. sshultz@unimelb.edu.au.
authors.forename: Sandy R
authors.initials: SR
authors.lastname: Shultz
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D011374:Progesterone