Use of Resveratrol to Decrease Acute Secondary Brain Injury Following Sports-Related Concussions in Boxers (REPAIR)

Use of Resveratrol to Decrease Acute Secondary Brain Injury Following Sports-Related Concussions in Boxers

Use of Resveratrol to Decrease Secondary Brain Injury Following Sports-Related Concussions: a Double-Blind, Placebo-Controlled Study

Sports-related concussions are a serious problem in football, boxing, and other full contact sports. After experiencing consecutive concussions, there is an increase in neurological deficits that can lead to long-term cognitive problems (Dementia pugilistica). To combat this increase in brain damage, novel strategies need to be developed to protect athletes that are participating in these full contact sports. The purpose of this study is to elucidate whether resveratrol decreases brain injury and improves brain function after experiencing a concussion in boxers.

Each year, approximately 3 million sports-related concussions occur in athletes. Only about 5% of these concussions are treated in the hospital setting. To date, there are no effective interventions used at decreasing the levels of oxidant injury and inflammation within these athletes. The standard form of care in these athletes is usually rest and light exercise for 1 -2 weeks, before returning to the sport. Within this brain injury population, administration of a neuro-protectant agent immediately following the concussion may alleviate or prevent secondary injury and subsequent development of long-term cognitive deficits such as Chronic Traumatic Encephalopathy (CTE) and Dementia pugilistica (DP). Since sports-related concussions are a serious problem in our youth, by using safe interventions, we believe that the levels of oxidant injury and brain inflammation will be decreased. In addition, these neuro-protective agents may improve cognition in these boxers, and decrease the incidence of DP. Following brain injury, the secondary injury that immediately follows consists of heightened damage by oxygen radicals, which in turn damages vital lipids, proteins, and nucleic acids. This damage is exacerbated by highly acidic conditions with lead to the release of iron and the production of more harmful oxygen radicals. An increase in these oxygen radicals has been observed from minutes to hours within the primary injury. In addition, there is an increase in inflammation as well as excitotoxicity in the brain after traumatic injury. To combat this secondary injury, the use of anti-oxidants in individuals is warranted to decrease the amount of brain damage and cognitive decline after experiencing a severe brain injury. For example, resveratrol (3,5,4'-trihydroxystilbene) which is a polyphenol compound that is commonly found in grapes, is a nutritional supplement with anti-oxidant and anti-inflammatory properties with great promise for treating TBI secondary injury. A number of researchers have demonstrated that resveratrol protect multiple organs (heart, kidney, brain) from ischemia after injury. With respect to the brain, resveratrol has been shown to protect from oxidative stress, Huntington's disease, and stroke. Additionally, following TBI in various animal models, resveratrol protected from severe brain injuries. Results from these brain studies suggest that resveratrol protects from a plethora of injuries and may afford protection from secondary injury in individuals suffering from a severe brain injury. In this pilot clinical trial, boxers (n=30) will be consented to participate in this study prior to engaging in a boxing match. The concussion history will be collected before enrolling. Baseline cognitive testing and magnetic resonance imaging (MRI) scan will be performed to obtain both structural and functional data. Only 12 boxers that have a concussion will be enrolled in this study. After participating in the boxing match, if the boxer has been diagnosed with having a concussion by the ringside physician, the boxers will be treated with an oral dose of the active trans-resveratrol (500 mg) or placebo within 2 hours of completion of the boxing match. The boxer will be treated with either resveratrol or placebo (depending on the randomization schedule) once a day for 30 days. Cognitive testing and MRI scans will be conducted on day 7 after the concussion.

The dose of resveratrol is 500 mg. The route of administration is oral, once-a-day for 30 days after injury.

The placebo is a sugar pill. The route of administration is oral, once-a-day for 30 days after injury.

Liver Function Testing (Aspartate Transaminase [AST]/Alanine Transaminase [ALT] Ratios) to Screen for Adverse Events.

Liver Function Testing (Aspartate Transaminase [AST]/Alanine Transaminase [ALT] Ratios) to Screen for Adverse Events.

Reaction Time Composite as Assessed by Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) Cognitive Test Performance

The reaction time composite score (range 0.5-0.8) is an average of: modules 3,4, 5, then divided by 3.The higher the composite score, the worse the outcomes. Average correct reaction time of interference stage of module 3 (X's and O'S) - Measures the number of correctly identified items (total possible correct =12), scoring 0-12. There is 4 trials of this module completed. Measures the average reaction time for correct responses on the interference (distracter) test Average correct reaction time of module 4 (Symbol Match) - Provides the number of correct matches out of 27 when the symbol number pairings are visible. The quicker the response time for each correctly identified symbol match indicates a better outcome. Average correct reaction time of module 5 (Color Match) - is number of correct color matches. The quicker the response time to a correct color match is a better outcome. Each modules is measured in percentage correct

Reaction Time Composite as Assessed by Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) Cognitive Test Performance

The reaction time composite score (range 0.5-0.8) is an average of: modules 3,4, 5, then divided by 3.The higher the composite score, the worse the outcomes. Average correct reaction time of interference stage of module 3 (X's and O'S) - Measures the number of correctly identified items (total possible correct =12), scoring 0-12. There is 4 trials of this module completed. Measures the average reaction time for correct responses on the interference (distracter) test Average correct reaction time of module 4 (Symbol Match) - Provides the number of correct matches out of 27 when the symbol number pairings are visible. The quicker the response time for each correctly identified symbol match indicates a better outcome. Average correct reaction time of module 5 (Color Match) - is number of correct color matches. The quicker the response time to a correct color match is a better outcome. Each modules is measured in percentage correct

Reaction Time Composite as Assessed by Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) Cognitive Test Performance

The reaction time composite score (range 0.5-0.8) is an average of: modules 3,4, 5, then divided by 3.The higher the composite score, the worse the outcomes. Average correct reaction time of interference stage of module 3 (X's and O'S) - Measures the number of correctly identified items (total possible correct =12), scoring 0-12. There is 4 trials of this module completed. Measures the average reaction time for correct responses on the interference (distracter) test Average correct reaction time of module 4 (Symbol Match) - Provides the number of correct matches out of 27 when the symbol number pairings are visible. The quicker the response time for each correctly identified symbol match indicates a better outcome. Average correct reaction time of module 5 (Color Match) - is number of correct color matches. The quicker the response time to a correct color match is a better outcome. Each modules is measured in percentage correct

Inclusion Criteria: Boxers between the ages 18-35 years old Both men and women Boxers with an estimated concussion (Mild and Moderate) as estimated by the on-site physician or athletic trainer Subject has provided full written informed consent prior to the performance of any protocol-specified procedure Exclusion Criteria: Immediate hospitalization for sports-related concussion (Severe Concussion) Known inclusion in an interventional clinical trial Patients with metal implants that would interfere with the MRI scan Known anemia Known Pregnancy Known history of alcohol/drug abuse