Recent Study in The FASEB Journal: Compound Reduces Brain Swelling and Inflammation After Traumatic Brain Injury

Recent Study in The FASEB Journal: Compound Reduces Brain Swelling and Inflammation After Traumatic Brain Injury

Traumatic brain injuries (TBI) from a fall or a hard blow to the head can lead to severe brain damage, muscle weakness, or death. Current treatments do not fix the underlying issues associated with TBIs, so there's a great need for more targeted therapies. In a recent preclinical study published in The FASEB Journal, researchers report that compounds that activate a receptor called smoothened reversed the inflammation, brain swelling, and neurological deficits associated with TBI. The findings could help researchers develop specific and effective treatments for TBI patients.

Every year in the U.S., about a million people are treated at emergency rooms for TBIs, and about 50,000 people die from the injuries or complicating factors, according to the International Brain Injury Association. Mild TBIs such as concussions can result from a hit to the head, a fall, car accident, or sports collision. Patients often experience nausea, sleep disturbances, or confusion in mild cases. However, patients with more severe TBI can lose consciousness, have memory loss, or die from the injury. When a TBI occurs, the brain may bounce or twist inside the skull, and the blood-brain barrier (BBB) that protects the brain from harmful substances is damaged, resulting in swelling and inflammation. Currently, most patients are put on bedrest or medications to alleviate symptoms, but no treatments exist that fix the underlying molecular causes.

"Smoothened" is a protein receptor involved in nervous system development. Activators of this receptor, such as the sonic hedgehog protein (Shh) and the small molecule called smoothened agonist (SAG), can improve neurological symptoms in TBI animal models, but Shotaro Michinaga and colleagues at Meiji Pharmaceutical University and Osaka Ohtani University wanted to determine if these proteins could also help repair the BBB and alleviate brain swelling and inflammation.

Through a series of experiments, the researchers showed that Shh administered directly into the cerebrospinal fluid of TBI animal models decreased BBB disruption, boosted factors that maintain the BBB, and reduced swelling and neuroinflammation markers. In brain-derived blood vessel cells in vitro, Shh enhanced the expression of tight junction proteins and other factors that help bolster the BBB.

Because Shh is a large protein, it might not enter the cerebrospinal fluid via intravenous injections commonly used in clinics. So, the team performed the same experiments with the small molecule SAG, which activates the same pathway as Shh. In tests, the researchers obtained similar results with the small molecule as they did with Shh. SAG administration also improved cognitive and motor function and balance in TBI animal models.

Overall, Shh and SAG improved BBB function and decreased swelling and inflammation in the brain through effects on several proteins and other factors. "These results suggest that smoothened agonists are potentially promising therapeutic agents for TBI," the authors say.

Funding: Japan Society for the Promotion of Science, Takeda Science Foundation, Research Foundation for Pharmaceutical Sciences

Read the full article, "Smoothened agonist treatment mitigates vasogenic edema, neuroinflammation, and neurological dysfunction following traumatic brain injury in mice," published in The FASEB Journal.