Long-term cognitive and neurodegenerative effects of repetitive mild traumatic brain injury

Abstract

1.6 – 3.8 million sports-related traumatic brain injuries (TBI) occur every year in the U.S. Recent retrospective studies suggest that repetitive mild TBI (rmTBI) is associated with the earlier onset of neurodegenerative diseases. Mild TBI can be hard to detect, and there are currently no widely accepted biomarkers that could aid in its diagnosis. Further, there is currently no standard pharmacological treatment for TBI. Our previous work demonstrated neurological deficits 1 week following 20-25 rmTBI in young male mice. We hypothesized that these deficits would persist up to 5 weeks following injury and that pretreatment with an agonist of the Sigma-1 receptor (PRE-084) could reduce these deficits, as has been demonstrated in other neurodegenerative models. Eight-week-old male C57BK6 mice were divided into sham injury, rmTBI, and rmTBI+PRE084 groups (n=14/gp). Mice were anesthetized and administered either PRE084 (1mg/kg sc) or vehicle immediately before experiencing closed head-injury with rotational acceleration via a 65g weight drop 5 days a week for 5 weeks. Five weeks after the final injury mice were assessed for neurological deficits. Injured mice demonstrated significant (P< 0.05) deficits in motor and vestibular-motor performance (Rotarod, balance beam) and cognitive performance in the Morris water maze. Treatment with PRE-084 did not ameliorate deficits. These data suggest there are chronic deficits for at least 5 weeks after rmTBI and that sigma-1 activation does not inhibit rmTBI deficits.