Traumatic brain injury (TBI) is a major cause of long-term disability in active-duty personnel and Veterans. Improvements in body armor have greatly reduced injuries to the vital organs and advances in emergency surgery have saved countless lives. Unfortunately, neurological dysfunctions following TBI represent one area where relatively little progress was made. TBI ranging from mild (concussions) to severe are produced in large numbers on the modern battlefield, especially as result of exposure to improvised explosive devices (IED) and paradoxically, improvements in other areas of emergency care has greatly increased the numbers of warfighters that live to experience the long-term negative effects of TBI. In spite of significant research efforts, no treatments for TBI have been shown to be to be clinically effective. At present, most acute post-TBI care is limited to supportive interventions and avoidance of repeat injuries with the hope that unaided physiological repair mechanisms will, over time improve the neurological dysfunctions. Unfortunately, large numbers of Veterans that have suffered TBI are left to cope with chronic neurological deficits including motor and cognitive impairments. It is imperative to propose and validate therapeutic strategies that would positively impact this large group of patients of particular importance to the VA system. Research has shown that TBI initiates multiple cascades of secondary molecular changes that cause delayed and progressive tissue damage, which lead to neurological dysfunction. Both intrinsic neuronal cell death mechanisms and secondary neurotoxicity following neuroinflammation are thought to contribute to the neuronal loss following brain trauma. Although much of the research focus has been directed at elucidating relatively early cellular and molecular events, experimental evidence suggests that the pathobiological processes initiated by TBI may continue for as long as a year or more after trauma- contributing to progressive neurodegeneration and chronic neurological deficits. Recent evidence suggests that persistent neuroinflammation following central nervous system (CNS) trauma lasts for months and even years, and may be responsible for chronic neurodegeneration and chronic neurological dysfunction. The goal of the proposed research is to demonstrate that the chronic secondary injury processes initiated by TBI and the secondary neurological deficits are not irreversible and represent a prime target for therapeutic intervention. This proposal is designed to test the hypothesis that delayed exercise and/or pharmacologic approaches targeting key secondary injury mechanisms can effectively reduce neuronal loss and neuroinflammation, and promote neuroplasticity responses resulting in attenuation of neurological dysfunction following TBI. The proposed studies designed to test our hypothesis will use a well-established animal experimental model of TBI, controlled cortical impact (CCI) in mice. This experimental TBI model mimics key pathophysiological mechanisms of the clinical TBI, and successful validation of our hypotheses in this model should increase the probability of clinical application. The proposed studies will determine: 1) Late exercise initiated after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI; 2) Late GGA administration initiated after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI; 3) Late PJ34 administration initiated after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI; and 4) Late combination intervention including the administration PJ34 or GGA with exercise after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI. .

Public Health Relevance

Large numbers of Veterans, particularly those returning from conflict zones have suffered from traumatic brain injury (TBI) and are left to cope with significant and long-lasting neurological dysfunctions. As no accepted therapeutic interventions exist for TBI, these Veterans receive only supportive care. Thus, it is imperative to identify effective treatment strategies that will target the secondary injury mechanisms that persist for month to years following TBI and successfully improve the chronic neurological dysfunctions. Previous studies suggest that exercise may be able to attenuate chronic TBI-induced neurological dysfunctions. As the ability to intervene late after TBI is important, we propose to test the neuroprotective potential of delayed exercise and select pharmacologic interventions targeting neuroinflammation mechanisms both separately and in combination using a well-established experimental TBI model. We believe that by demonstrating the efficacy of exercise in this model we ensure a high clinical translation potential.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX001993-04
Application #
9795385
Study Section
Brain Health & Injury (RRD1)
Project Start
2016-07-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baltimore VA Medical Center
Department
Type
DUNS #
796532609
City
Baltimore
State
MD
Country
United States
Zip Code
21201