Serving those who serve through military medicine research

Texas A&M University was established in 1876 as a military institution, and Texas A&M’s Corps of Cadets consistently commissions more officers into the country’s military than any other school in the nation besides the three service academies. At the Texas A&M School of Medicine, this heritage of the flagship university inspired the creation of the Military Medicine Program, which has the mission of “preparing Aggie Doctors to lead military health care teams with integrity, resilience and unparalleled expertise.”

Although the Military Medicine Program has only been formalized in recent years, the endeavors of those at the Texas A&M School of Medicine to engage in military medicine started with the school’s creation more than four decades ago in conjunction with the Central Texas Veterans Health Care System. Many researchers have long-standing relationships with the U.S. Department of Defense (DoD) to identify pathogenic mechanisms and treatments for diseases that are relevant to the military. Two such examples are traumatic brain injury (TBI) and Gulf War Illness, which are currently being researched by D. Samba Reddy, PhD, RPh, in the Department of Neuroscience and Experimental Therapeutics, and Ashok K. Shetty, PhD, in the Institute for Regenerative Medicine and the Department of Cell Biology and Genetics.

Research on traumatic brain injuries in the military

Reddy, a Regents Professor, is the lead researcher of the Neuroscience and Experimental Therapeutics lab that has been awarded a DoD grant to identify a pharmaceutical treatment for the aftermath of traumatic brain injury (TBI). Severe TBI most often affects soldiers in the military who are subjected to major brain injuries due to blast injuries, falls or vehicular crashes. These injuries can lead to long-term effects such as memory loss, epilepsy and dementia, and patients have to take multiple medications for the rest of their lives to manage these often-debilitating symptoms. Additionally, once soldiers are diagnosed with TBI, they cannot operate heavy machinery or be re-deployed, which heavily impacts their career trajectories in the military.

Reddy’s lab was able to identify that these symptoms are induced by the HDAC (histone deacetylase) epigenetic pathway in the nucleus that is activated by TBI. Current treatments for TBI-induced epilepsy, including calcium-channel blockers and phenytoin, target the membrane to block ion channels or enzymes involved in neurotransmitter reuptake. However, the medication that Reddy’s lab is developing under the DoD grant is called an HDAC inhibitor, and blocks the HDAC epigenetic pathway in the nucleus that is activated by TBI.

About 70 percent of epilepsy patients have an unknown cause for their seizures, and Reddy is hopeful that the military-centric research being conducted for treating TBI-induced epilepsy at the source can be used to treat other forms of epilepsy for the general public in the future. On March 18, 2022, Reddy’s first synthetic neurosteroid, ganaxolone, was approved for genetic epilepsy. He shared that he is looking forward to adding this new medication to his lecture on antiseizure medications that he teaches the first-year medical students every year, as it is a representation of the direct results of the last 18 years of his research. As a licensed pharmacist, Reddy emphasized that while research is fulfilling in its own right, he sees the true impacts of his work “when I go to a pharmacy and see my medicine sitting there on the shelf, knowing that people are benefiting from it.”

Shetty, professor and associate director at the Institute for Regenerative Medicine in the Department of Cell Biology and Genetics, is developing a biologic comprising mesenchymal and neural stem cell-derived extracellular vesicles for preventing dementia and mood impairments after mild to moderate TBI. His recent National Institute of Neurological Disorders and Stroke (NINDS) funded study demonstrated that a single intranasal dose of mesenchymal stem cell-derived extracellular vesicles after TBI can prevent long-term cognitive and mood impairments, which was published in the journal Brain Behavior and Immunity. Shetty said this patented technology promises to prevent dementia and neuropsychiatric disorders in military and civilian populations incurring mild to moderate TBI.

Research on Gulf War Illness

Shetty is also the lead researcher for a Gulf War Illness (GWI) research program funded by five active grants from the Department of Defense. Gulf War illness is observed in veterans who were exposed to chemical warfare agent antidotes and/or pesticides in the first Gulf war as well as during the Afghanistan and Iraq wars. It manifests with symptoms such as cognitive and mood impairments, fatigue, headaches, joint pain, irritable bowel syndrome, insomnia, dizziness, respiratory disorders and skin problems.

In Shetty’s lab, they seek to understand the long-term pathophysiology of GWI with the goal of identifying treatments in animal models that can be translated to clinical care for veterans. Their research focuses on repurposing existing Food and Drug Administration (FDA)-approved drugs to treat GWI and has found that montelukast, which is traditionally used as an anti-asthmatic, and cannabidiol are both effective in treating the symptoms of GWI in animal models.

The use of montelukast to treat GWI is moving to a DoD-funded clinical trial in collaboration with an investigator at the Baylor College of Medicine (Drew Helmer, principal investigator; Ashok Shetty, co-principal investigator and subcontract principal investigator). In this clinical trial, Helmer’s research group is recruiting veterans with GWI and treating them with montelukast to test its effects on their cognitive function, while Shetty’s research group will track neuroinflammation in these veterans with GWI receiving montelukast treatment by investigating changes in the composition or cargo of brain-derived extracellular vesicles in their blood.

When asked how these findings can improve health outcomes for the general public, Shetty said, “If montelukast successfully alleviates symptoms of GWI, the drug could also be used in non-GW veterans exhibiting GWI-like symptoms. In the general population, people exposed to significant levels of chemicals such as pesticides, insecticides and organophosphates (e.g., pesticide/insecticide applicators) likely also exhibit GWI-like symptoms. Hence, any treatment developed for GWI could potentially be employed for civilian populations exposed to multiple chemicals and exhibiting GWI-like symptoms.” 

Collaboration between the DoD and Texas A&M School of Medicine

These researchers have shown very promising results in their respective fields of research, and although this success is rewarding from an academic standpoint, they both find their motivation to continue doing this work even after two decades because they are truly making a difference in the lives of so many veterans and other patients ailed with these conditions.

Shetty shared that his motivation to conduct military medicine research “is not about getting research articles published consistently or securing large grants. The real success is in helping to find a cure for illnesses affecting veterans or at least improving their quality of life through research. Understanding the mechanisms underlying these illnesses and developing potential treatments can improve the quality of life of veterans who have served our country well.”

Reddy views his research as a means to protect the countless heroes who protect us every day, as he shared that “whether military or first responders—such as firefighters, police and EMS—they are in dangerous situations and experience brain injuries, and will need some medicines to protect them. They’re all protecting us, so this is how my team and I can meet a need for them.”

As they continue to quickly progress towards finding a cure for conditions that heavily impact those in the military and also have implications for the general public, Shetty and Reddy both share the sentiment that Texas A&M is uniquely positioned to make great advancements in military medicine. They look forward to much more collaboration between the School of Medicine and the DoD in the future.