Mayland Chang in the Department of Chemistry and Biochemistry at the University of Notre Dame has received a grant from NFL Charities to design and develop therapeutics for the treatment of traumatic brain injury. NFL Charities, the charitable foundation of the National Football League owners, has awarded more than $1.6 million in grants to support sports-related medical research at 16 organizations, including the University of Notre Dame. Of these grants, $988,224 will go to research groups studying concussion prevention and treatment.
Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialized world. Concussions are a common concern in sports, with 300,000 reported concussions in the US occurring while playing sports and with football accounting for the highest proportion of concussions in high school athletes. Concussions result from a blow to the head that produces a cascade of neurological events, resulting in reduced blood flow to the brain, neuronal cell injury, and death. A contributing factor to these pathological processes is the activation of matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2 and MMP-9).
"Research in the field presently lacks the ability to rescue brain cells after each concussion or any damage to the brain," says Maylang Chang. “If a medication could be given after such a damage that rescues the brain cells destined to die, that would move the field forward in treatment of TBI significantly. We are proposing ground-breaking research that has the potential for the development of such a treatment for TBI.”
Chang is working with Zezong Gu, assistant professor of neuroanatomy and neuroscience at the University of Missouri to design water-soluble gelatinase inhibitors. They hypothesize that selective mechanism-based inhibition of MMP-9 activity prevents brain proteolysis of basal membrane components and rescues neurons from the consequences of TBI. They plan to design a water-soluble gelatinase inhibitor variant of SB-3CT that would advance to preclinical development and clinical trials for the treatment of TBI.
The highly selective mechanism-based gelatinase inhibitor SB-3CT is effective in preventing proteolysis of basal membrane laminin and can rescue neurons from ischemia-induced brain injury and apoptosis. Most importantly, significant therapeutic activity of SB-3CT is seen up to 6 hours after initial brain damage. Mechanism-based gelatinase inhibition could protect the neurovascular integrity of the brain from TBI by blocking degradation of the basal membrane components such as laminin, exerting anti-apoptotic effects on neurons, reducing brain edema, and preventing apoptosis. Therefore, treatment with selective mechanism-based gelatinase inhibitors holds great promise for minimizing neuron damage and brain swelling associated with TBI.
NFL Commissioner Roger Goodell, President of the NFL Charities Board, says, “We are proud to support sports-related medical research proposals through NFL Charities Medical Research Grants. These grants will help to address risk factors for football players and all athletes, and make the game safer.”
The NFL has supported sports-related medical research for decades through NFL Charities medical research grants. Since 2000, NFL Charities has funded grants for studies on brain injury, ACL injury prevention and heat stress risks. Other studies funded this year include research on the association between football exposure and dementia in retired football players; the dynamic heart rate behavior of NFL athletes; the prevalence, distribution and fate of MRSA on synthetic turf grass systems; concussion surveillance among a large national sample of middle school football players; the role of cervical spine in football-related concussion; and an integrated neuroimaging study for diagnosing and monitoring mild TBI in football players.