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New Research Suggests Blocking a Pathway in the Brain Can Help Treat Traumatic Brain Injury Symptoms

By Ezgi Coskun

Graphic design by Qingyue Guo

Blocking a single enzyme in the brain may reduce anxiety-like behaviours and memory problems after traumatic brain injury (TBI), according to new research from Dr. Aylin Y. Reid’s lab at the University Health Network (UHN).1 In a rat model of TBI, blocking indoleamine 2,3 dioxygenase 1 (IDO1), an enzyme that activates the kynurenine pathway after injury,2 improved post-injury behavioural outcomes.1 The findings suggest that targeting this pathway may represent a potential therapeutic strategy for the millions of people affected by TBI each year. 

Each year, over 50 million TBI cases are reported worldwide.3 The most common causes of TBI include falls, vehicle accidents, and sports.4 According to the Canadian Hospitals Injury Reporting and Prevention Program, approximately 45% of reported head injuries were TBI (291,465 cases), and 15% of these cases involved children from the age of 5 to 19 participating in sports.4 

Despite its prevalence, there is no definitive treatment for TBI. Many survivors continue to struggle after injury, experiencing anxiety, memory problems, mood changes, and in severe cases, post-traumatic epilepsy (PTE), which is characterized by recurrent and spontaneous seizures.5

When Emma*, a 13-year-old high school student from London, Ontario collapsed during a football tournament two years ago; her parents experienced their worst fear. “We just thought it was a concussion,” her mother said. “But then the memory issues and anxiety started, then seizures. She was a perfect A-student before.” What Emma and her family went through reflects what many TBI survivors face: untreated neurological diagnoses, loss of independence, and decreased quality of life. 

To better understand these long-term effects and develop treatments for patients like Emma, researchers in Dr. Reid’s lab are investigating the biological pathways contributing to neurological dysfunction after TBI. The team chose to study the kynurenine pathway, a major metabolic pathway that breaks down tryptophan to produce metabolites that regulate inflammation, oxidative stress, and communication between brain cells.6

According to Dr. Reid, the lab chose this pathway because “[it] has been implicated in a number of neurological disorders. Activation of this pathway can lead to increased inflammation and oxidative stress in the brain. While there is evidence that activity in this pathway is increased after TBI, no one had tried targeting this pathway with drugs after injury to see if it led to improvement.” 

The researchers focused on IDO1 because it acts as a key gatekeeper in the biochemical pathway that becomes overactive after the injury.2 After a TBI, inflammation acts as a defense mechanism to protect the brain. This inflammation influences how the body processes the amino acid tryptophan. 

Tryptophan is the building block of serotonin, our “happy” neurotransmitter that regulates mood, sleep, learning, memory, and seizure susceptibility.7,8 However, following TBI, inflammation increases activity of the kynurenine pathway, diverting more tryptophan away from neuroprotective serotonin production and toward the generation of kynurenine metabolites, some of which are neurotoxic.2 Studies have shown that an imbalance between neuroprotective and neurotoxic tryptophan metabolites is associated with psychological disorders as well as PTE.1,2 

The IDO1 enzyme drives this shift,2 and acts as a guard that opens the door to the kynurenine pathway. During inflammation, production of IDO1 increases. This makes the kynurenine pathway more active, producing more downstream metabolites like neurotoxic quinolinic acid, which has been shown to increase after TBI.2 

Using a rat model of TBI, Dr. Reid’s team showed that blocking the IDO1 enzyme, which catalyzes the first step of the kyneurenine pathway, reduced the production of neurotoxic tryptophan metabolites and improved anxiety-like behaviour and memory in male rats after injury.1 These findings suggest that excessive activation of the kynurenine pathway through IDO1 may contribute to long-term neurological symptoms observed after TBI. 

“TBI is a complicated disorder and can cause very different outcomes from one person to another,” Dr. Reid explained. “So far there are no treatments that are effective at improving neurological outcomes after TBI. Our work with IDO1 inhibition after TBI supports a role for the kynurenine pathway in some of the negative outcomes after TBI, and shows promise as a target for new treatments.”

Dr. Reid emphasized that this research is still in its early stages. “There is still a lot to learn, such as how individual parts of this pathway contribute to outcomes, and whether there are any negative effects to targeting this pathway,” she said. 

Building on this work, the team is replicating their studies in female rats and investigating whether the benefits observed after IDO1 inhibition are the result of increased activity in the kynurenine pathway or from shunting tryptophan toward serotonin production. The lab is also exploring the impact of IDO1 inhibition on additional TBI symptoms. With support from the Canadian Institutes of Health Research, the lab is investigating whether targeting this pathway could help prevent seizures and the development of PTE, while also developing brain imaging approaches to identify biomarkers that may help clinicians assess injury severity earlier and more accurately. Together, these insights could improve both treatment and diagnosis of TBI.  

Although the research is still in early stages, it provides insight into the biochemical mechanisms underlying long-term symptoms after TBI and highlights a promising avenue for future therapies. The ultimate goal is to translate these findings into treatments that will improve patients’ quality of life after injury. “The future of this area of research lies in developing a drug that can ameliorate the adverse effects of TBI in both the short- and long-term,” said Marawan Sadek, the research assistant who led the study in Dr. Reid’s lab. Sadek added that “such a drug would be beneficial in reducing, or ideally eliminating, the memory, motor, and mood deficits caused by severe TBI.”

*Name changed for privacy reasons. 

References

  1. Sadek M, Stover KR, Liu X, et al. IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats. J Neurosci Res. 2024;102(5):e25338.
  2. Meier TB, Savitz J. The Kynurenine Pathway in Traumatic Brain Injury: Implications for Psychiatric Outcomes. Biol Psychiatry. 2022;91(5):449–58.
  3. Yu T, Liu X, Sun L, et al. Clinical characteristics of post-traumatic epilepsy and the factors affecting the latency of PTE. BMC Neurol. 2021;21(1):301.
  4. Canada PHA of. Traumatic Brain Injuries – Canada.ca [Internet]. 2024 [cited 2025]. Available from: https://health-infobase.canada.ca/brain-injuries/
  5. Kureshi N, Clarke DB, Feng C. Association between traumatic brain injury and mental health care utilization: evidence from the Canadian Community Health Survey. Inj Epidemiol. 2023;10(1):16.
  6. Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25(1):131–47.
  7. Sourbron J, Lagae L. Serotonin receptors in epilepsy: Novel treatment targets? Epilepsia Open. 2022;7(2):231–46.
  8. Li Y, Hu N, Yang D, et al. Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism. FEBS J. 2017;284(6):948–66.