Texas A&M researcher awarded DOD grant to develop drug for brain injuries

More than 400,000 soldiers were diagnosed with traumatic brain injury (TBI) between 2000 and 2018, but this number is assumed to be an underestimate due to underreporting or misdiagnosis. D. Samba Reddy, PhD, RPh, a Regents professor in the department of Neuroscience and Experimental Therapeutics in the Texas A&M University School of Medicine, is the lead researcher of a lab that has been awarded a U.S. Department of Defense (DOD) grant to identify a pharmaceutical treatment for the aftermath of TBI.

TBI is a serious injury to the brain brought on by an external force, frequently as a result of a head injury or a sudden, violent movement of the head. When someone has a TBI, they may not experience symptoms right after the blunt force, but the injury can wreak havoc on the brain because the brain’s neurons are very fragile and can be broken, or the synapses between them can be permanently dislocated. This leads to persistent headaches, memory loss or even loss of consciousness because the part of the brain that controls consciousness goes into shock, and the action potentials—which are how neurons communicate with each other—come to a standstill. People with TBI are at high risk for dementia, epilepsy and Alzheimer’s disease.

TBIs are categorized into three classes—mild, moderate and severe—which are determined by loss of consciousness, length of memory loss and responsiveness after the injury. Mild TBIs are more commonly known as concussion but can have some serious lasting effects despite their classification. Moderate TBIs are associated with vehicular crashes or sports-related collisions and often result in internal bleeding in addition to a concussion. Severe TBIs are most often brought on by incidents in military service, such as explosions or falls, which can lead to concussion, internal bleeding, skull fracture and hemorrhage. In the case of blast injuries, shrapnel produced by the explosion can cause further injuries and exacerbate the symptoms of the severe TBI.

How do TBIs affect soldiers?

“Soldiers will come home, and after two to four years, they start showing signs of brain damage and seizures, called post-traumatic epilepsy,” Reddy said. “This is a lifelong condition—once they get diagnosed, they can never be re-deployed and cannot operate heavy machinery, which heavily impacts their careers.”

The life expectancy of those with post-traumatic epilepsy is 50 to 60 years, but even if their seizures are well controlled, they deal with many side effects from the many medications they must take for the rest of their lives. Additionally, when soldiers get this diagnosis, many of them go into depression and need to take psychiatric medications in addition to their epileptic medication. Tragically, some of them end up losing their lives to suicide.

Those who experience severe TBI are at the highest risk for epilepsy, memory loss and dementia. Up to 25 percent of all individuals who have a moderate to severe brain injury will have epilepsy, and Reddy said that “most people think that if you have a seizure, you recover, and there’s no problem as long as you make sure you don’t get hurt yourself. Very many people don’t know that seizures could kill—this is known as sudden unexpected death in epilepsy.”

How can TBI-induced epilepsy be treated?

Many medications for epilepsy, such as sodium-channel blockers or phenytoin, target the membrane to block ion channels or enzymes involved in neurotransmitter reuptake. Most TBI-induced epilepsy cases are resistant to medication, because when there is widespread damage to the brain, there are likely not enough ion channels or receptors to respond to the medication. Reddy’s approach to treating TBI-induced epilepsy is to address the cause at the root, which is the HDAC (histone deacetylase) epigenetic pathway in the nucleus of the cell.

Using an animal model that he recently created with a brain injury, Reddy’s lab showed that the HDAC epigenetic pathway is responsible for many of the aftereffects of TBI, such headaches and memory loss, along with dementia and epilepsy, among others. Then they inhibited the hyperactivation using an HDAC-inhibiting medicine and were able to prove that not only can HDAC activation be inhibited, but the downstream effects of this pathway—neuroinflammation, brain damage, memory loss, seizures and depression—can be effectively alleviated.

Reddy’s lab presented this discovery to the DOD and were awarded a new grant to build off their findings to develop a treatment for TBI. The proposed therapies would allow for immediate treatment on the battlefield or the scene of an accident to prevent the HDAC epigenetic pathway from even being activated in the first place and prevent long-term consequences.

“If you can inhibit hyperactivated epigenetic target at all, the devastating chronic impact can be prevented, and acute recovery will be much faster,” Reddy said.

At present, the HDAC inhibitors used for research are repurposed HDAC inhibitors to treat cancer, because neuronal HDAC inhibitors have yet to be identified. Reddy’s goal is to find HDAC inhibitors to target the brain specifically and avoid the side effects that come with the repurposed drugs.