The Long-Term Neurodegenerative Effects of Repetitive Mild Traumatic Brain Injury and Treatment With Sigma-1 Receptor Agonist PRE-084

An estimated 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 the diagnosis of mTBI. 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 some of these deficits would persist up to 5-15 weeks following injury and that treatment 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 + Vehicle, rmTBI + Vehicle, and rmTBI+PRE084 groups (n=10/gp). Mice were lightly anesthetized with isoflurane and administered either PRE084 (1mg/kg sc or ip) or vehicle immediately prior to experiencing closed head-injury with rotational acceleration via a 65g weight drop 5 days a week for 5 weeks. Five (group 1) and fifteen weeks (group 2) after the final injury mice were assessed for neurological deficits. Injured mice in test 1 demonstrated significant (P<0.05) deficits in motor and vestibular-motor. Wake times were significantly increased (P<0.05) for Hit mice in both tests one and two. However, cognitive performance in T-maze active avoidance, anxiety-related behavior in the elevated plus maze, and Water Maze on group 1 were not affected. Water maze data on group 2 yielded significant results (P<0.05) indicating both groups of Hit mice performed worse on percent time in annulus 40 centimeters, and on path length in trials one and three. Treatment with PRE-084 did not ameliorate any of these deficits. On group 2, Hit + PRE-084 mice performed significantly worse than their counterparts on the rotarod test. The data suggest that there are some chronic deficits for at least 5 weeks after rmTBI, and that sigma-1 activation does not reverse negative effects of rmTBI. Ongoing studies are examining the persistence of these deficits in mice 15 weeks after the final injury, which are relevant to rmTBI related deficits in military personnel that persist up to a year. Water maze data is beginning to persistent deficits due to rmTBI in the long-term.