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).
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.