It is very important to uncover therapeutic strategies to combat the chronic effects of traumatic brain injury (TBI) because currently, there are no effective treatments to prevent these cognitive deficits. Unfortunately, TBI is a very common affliction of military forces that have served in recent combat operations. At least 15% of deployed personnel receive a TBI and the total number of such injuries has been estimated as high as 320,000. In the US alone it is estimated that at least 1.7 million people suffer a TBI each year and the worldwide incidence is approximately 0.5% per year. The vast majority of TBIs experienced by military personnel are classified as mild injuries, but these do result in significant, chronic effects. We seek to demonstrate an effective treatment that could reduce or reverse the long-term cognitive dysfunction that is produced by mild traumatic brain injury (TBI). Because these injuries involve multiple effects, it is necessary to further characterize the treatment effects on the lasting dendritic and spine changes induced by TBI and add to our knowledge of therapeutic changes that are possible so that TBI patients will benefit. Over the past several years, our lab has discovered that an activator of an antioxidant transcription factor, Nrf2, can be neuroprotective by regulating molecular mechanisms that are important to the health of neurons. This has led us to formulate a hypothesis that treatment of mild traumatic brain injury with the Nrf2 activator wil result in significant improvement on the connections between neurons, promote neuroprotective intracellular pathways, and result in greatly enhanced long-term outcomes following TBI. We will test our hypothesis with three specific aims: 1. Prevention of the chronic behavioral effects of mild closed head injury by tBHQ treatment, 2. Improvement of persistent connectivity changes produced by tBHQ treatment after mild TBIs, and 3. Identify molecular changes induced by the post TBI treatment that could influence long-term function. We will examine changes to molecular and long-term cognitive function after mild TBI accomplished by the closed head impact injury model in mice. We will use a well-established TBI model involving a closed head injury model that does include rotation. We will treat injured and sham injured groups with either vehicle or tBHQ. Behavioral tests will be conducted at 1, 6, and 12 months after injury. Brain samples will also be collected and examined for dendritic complexity, spine density, and neuron numbers. Finally, levels of neuropathological pathway markers will be examined at early and late (12 month) time points, all to study the effects of the post-injury treatment. In this way we will answer several key questions about the treatment of the long-term effects of mild traumatic brain injury, how the treatment will affect molecular events that have lasting consequences after injury, what happens to dendritic complexity after treatment at lengthy times after mild injury, and the extent to which the treatment induced changes in specific regulatory factors can have an effect on downstream neuronal function. Elucidating the effects of the treatment after mild traumatic brain injuries over a year following the injury will help us determine an effective therapeutic solution to the problem of chronic TBI effects.

Public Health Relevance

Traumatic brain injury is currently untreatable and has persistent effects on patients, families, and our healthcare system. Approximately 1.7 million people suffer this kind of brain injury in the US each year. As the signature affliction of current deployed forces, as many as 320,000 military personnel have received these injuries while serving in recent combat operations overseas. Unfortunately, an effective treatment is still needed. Towards that goal, we are testing a treatment that could improve the long-term outcome after mild traumatic brain injury. We seek to demonstrate the efficacy with a closed head injury model, and this study will also enhance our understanding of the mechanisms that contribute to TBI induced neurodegeneration. With the proposed treatment, we hope to block biological processes contributing to injury-induced loss of neuronal function in the brain and prevent the lasting consequences of these injuries.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX001520-03
Application #
9110903
Study Section
Brain Injury: TBI & Stroke (RRD1)
Project Start
2014-07-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Bay Pines VA Medical Center
Department
Type
DUNS #
781692777
City
Bay Pines
State
FL
Country
United States
Zip Code
33744
Citron, Bruce A; Ameenuddin, Syed; Uchida, K et al. (2016) Membrane lipid peroxidation in neurodegeneration: Role of thrombin and proteinase-activated receptor-1. Brain Res 1643:10-7
Citron, Bruce A; Saykally, Jessica N; Cao, Chuanhai et al. (2015) Transcription factor Sp1 inhibition, memory, and cytokines in a mouse model of Alzheimer's disease. Am J Neurodegener Dis 4:40-8