Concussions or mild traumatic brain injuries (mTBI) account for 75% of all TBIs and often result in cognitive and neuropsychiatric impairment with those sustaining repeated mTBIs (rmTBI) having a worse prognosis. The vast majority of individuals acquiring a single mTBI recover in approximately 1 week without intervention which is not the case for rmTBI. Thus there is an unmet need for improved understanding of the spontaneous repair mechanism after single mTBI that is impaired with repeated mTBI and a need for the development of therapies to reduce damage and promote recovery after rmTBI. Previously, our lab and others have shown that neurogenesis is enhanced after a single mTBI; however, it has not been examined after repeated mTBI. Neuroinflammation, which is present after mTBI, has been demonstrated to alter neurogenesis. Two of the major contributors to neuroinflammation are nuclear factor kappa B (NF-?B) and reactive oxygen species (ROS). Intriguingly, we have characterized a novel catalytic oxidoreductant, the metalloporphyrin manganese (111)-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+), that both dissipates ROS and inhibits the activation of NF-?B. Therefore, we hypothesize that simultaneously targeting multiple secondary injury mechanisms to reduce neuroinflammation after rmTBI will mitigate deficits and enhance recovery by promoting neurogenesis. To test this idea we will 1) Evaluate the hypothesis that administration of MnTE-2-PyP5+ after rmTBI will reduce neuroinflammation and confer tissue protection by dissipating ROS and inhibiting NF-?B signaling; 2) Test the hypothesis that post-mTBI administration of MnTE-2-PyP5+ helps alleviate rmTBI-induced deficits in cognition, emotion, and behavior; and 3) Assess the hypothesis that post-mTBI administration of MnTE-2-PyP5+ will promote neurogenesis after rmTBI.
These aims will be achieved using diverse analytical techniques including a clinically-relevant impact-acceleration mTBI model; biochemical analysis of activated NF-?B and markers of oxidative stress; histological assessment of neuroinflammation and tissue damage; behavioral evaluation of cognition, sleep, and neuropsychiatric symptoms; immunofluorescence analysis of neurogenesis in transgenic mice with selectively labelled newborn granule cells; and morphological assessment of newborn neurons. These experiments are expected to elucidate the interaction between neuroinflammation and neurogenesis after rmTBI, as well as offer a potential therapeutic that could halt the secondary injury cascade and promote functional recovery. The proposed training plan for the PI includes weekly participation in lab meetings, journal clubs, and seminars. The PI will also partake in a graduate trainee seminar series with directed feedback from faculty and peers and present at a national scientific meeting, annually. Formal and informal training in ethical practices in scientific inquiry will be continued. Additionally, the PI will meet regularly with the sponsor Dr. Candace Floyd and bi-annually with committee members for continued mentorship.
Traumatic brain injury (TBI) is a major health concern in the U.S. with an estimated 2.5 million new cases each year; 75 percent of which are mild TBIs (mTBI). Cognitive, emotional, and behavioral alterations are common problems after mTBI, with those sustaining repeated mTBIs (rmTBI) having a much worse prognosis. The proposed study is designed to investigate the mechanisms contributing to impaired recovery after rmTBI and evaluate the ability of a therapeutic to target those mechanisms to treat rmTBI.
