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

Kyria M Webster,Sandy R Shultz,Ezgi Ozturk,David K Wright,Terence J O'Brien,Donald G Stein,Mujun Sun,Bridgette D Semple

doi:10.1186/s12974-015-0457-7

Abstract

BackgroundRepeated 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.MethodsMale 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.ResultsRepeated 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.ConclusionsThese 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.

Highlights

Repeated mild traumatic brain injuries, such as concussions, may result in cumulative brain damage, neurodegeneration and other chronic neurological impairments
We report that PROG treatment in repeated mTBI (rmTBI) significantly reduced neuroinflammation, oxidative stress, brain damage and cognitive and motor impairments
Post hoc analysis found that repeated mild fluid percussion injury (rFPI) + vehicle treatment (VEH) rats performed fewer direct and circle swims than all other groups (p < 0.05), whereas the rFPI + PROG group did not significantly differ from either of the sham injury (SHAM) groups

Summary

Introduction

Repeated mild traumatic brain injuries, such as concussions, may result in cumulative brain damage, neurodegeneration and other chronic neurological impairments. Neuroinflammation is common in TBI patients, as well as in other neurodegenerative conditions associated with mTBI, including Alzheimer’s disease and motor neuron disease [8, 9]. Both our laboratory and others have observed elevated and persisting neuroinflammation and oxidative stress in experimental models of mTBI, which coincides with progressive brain damage and chronic behavioural abnormalities [7, 10,11,12,13,14,15,16,17]

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