Although much progress has been made in the development of body armor and military trauma medicine, there have been only two successful clinical trials in the last 40 years to find safe and effective pharmacotherapies to treat or prevent the complex pathophysiology associated with TBI. Prophylactic therapies represent a powerful pharmacological approach to deal with TBI pathology that has not yet received widespread attention. This approach could be uniquely valuable in high-risk populations such as our current military personnel. To be effective in a military field setting, prophylactic compounds must have excellent safety profiles;they must be well tolerated;and easily administered. Given these constraints, dietary supplements such as nicotinamide (NAM) and neuroactive steroids like allopregnanolone (ALLOP) would be ideal candidates. We have chosen to investigate these compounds based on their multifunctional nature, demonstrated efficacy in pre-clinical research, as well as their relative safety and availability. NAM and ALLOP have both been shown to ameliorate numerous TBI-related pathophysiological processes and improve recovery of behavioral function when administered post-injury. Although they have not been expressly tested as prophylactic agents in TBI, there is evidence that pre-injury administration of NAM or neurosteroids (e.g., progesterone) has beneficial effects on recovery of function following experimentally induced ischemia. Given the significant overlap in pathophysiology of ischemic stroke and TBI, there is reason to hypothesize that pretreatment with NAM, ALLOP or NAM+ALLOP will ameliorate the effects of TBI in a rodent model of closed head injury. The primary objective of this project is to investigate the prophylactic effects of allopregnanolone (ALLOP) and nicotinamide (NAM) in a combination therapy study using a pre-clinical animal model of TBI. These studies are designed to evaluate the prophylactic effects of NAM, ALLOP, and NAM+ALLOP on functional recovery (Aim1), physiological impairment such as neurodegeneration (Aim 2) and pathophysiological mechanisms of secondary injury including neuroinflammatory cytokines, and markers of apoptosis (Aim 2).

Public Health Relevance

Traumatic brain injury is a significant problem for military personnel currently serving in Iraq and Afghanistan. These individuals are our VA patients of the future. The discovery of safe and effective compounds that mitigate TBI-related pathophysiology will bring considerable benefit to the morbidity, mortality, disability, personal and economic costs associated with TBI. In this proposal we will assess the prophylactic efficacy of nicotinamide (NAM), allopregnanolone (ALLOP) and the combination (NAM+ALLOP) on functional and physiological measures of injury as well as the underlying pathophysiological mechanisms of secondary injury. We will also compare prophylaxis to post-injury administration of these compounds and assess outcomes at short and long term recovery points.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2BX001267-03
Application #
8598044
Study Section
Neurobiology C (NURC)
Project Start
2011-10-01
Project End
2016-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Durham VA Medical Center
Department
Type
DUNS #
043241082
City
Durham
State
NC
Country
United States
Zip Code
27705
Miller, Kelsey M; Risher, Mary-Louise; Acheson, Shawn K et al. (2017) Behavioral Inefficiency on a Risky Decision-Making Task in Adulthood after Adolescent Intermittent Ethanol Exposure in Rats. Sci Rep 7:4680
Risher, Mary-Louise; Fleming, Rebekah L; Risher, W Christopher et al. (2015) Adolescent intermittent alcohol exposure: persistence of structural and functional hippocampal abnormalities into adulthood. Alcohol Clin Exp Res 39:989-97
Klein, Rebecca C; Acheson, Shawn K; Mace, Brian E et al. (2014) Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice. Neurobiol Aging 35:2046-52
Centanni, Samuel W; Teppen, Tara; Risher, Mary-Louise et al. (2014) Adolescent alcohol exposure alters GABAA receptor subunit expression in adult hippocampus. Alcohol Clin Exp Res 38:2800-8
Swartzwelder, H S; Hogan, A; Risher, M-Louise et al. (2014) Effect of sub-chronic intermittent ethanol exposure on spatial learning and ethanol sensitivity in adolescent and adult rats. Alcohol 48:353-60
Klein, Rebecca C; Saini, Shyla; Risher, M-Louise et al. (2014) Regional-specific effects of ovarian hormone loss on synaptic plasticity in adult human APOE targeted replacement mice. PLoS One 9:e94071
Acheson, Shawn K; Bearison, Craig; Risher, M Louise et al. (2013) Effects of acute or chronic ethanol exposure during adolescence on behavioral inhibition and efficiency in a modified water maze task. PLoS One 8:e77768
Li, Qiang; Fleming, Rebekah L; Acheson, Shawn K et al. (2013) Long-term modulation of A-type K(+) conductances in hippocampal CA1 interneurons in rats after chronic intermittent ethanol exposure during adolescence or adulthood. Alcohol Clin Exp Res 37:2074-85
Fleming, Rebekah L; Li, Qiang; Risher, Mary-Louise et al. (2013) Binge-pattern ethanol exposure during adolescence, but not adulthood, causes persistent changes in GABAA receptor-mediated tonic inhibition in dentate granule cells. Alcohol Clin Exp Res 37:1154-60
Risher, Mary-Louise; Fleming, Rebekah L; Boutros, Nathalie et al. (2013) Long-term effects of chronic intermittent ethanol exposure in adolescent and adult rats: radial-arm maze performance and operant food reinforced responding. PLoS One 8:e62940

Showing the most recent 10 out of 13 publications