Researchers may have solved decades-old mystery behind benzodiazepine side effects

Benzodiazepines like Valium and Xanax are often prescribed to treat anxiety, insomnia and seizures. While these drugs can be effective as a short-term treatment, researchers are trying to better understand the impact of benzodiazepines after extended use.

Some experts believe long-term use of the medication may influence inflammation levels in our bodies, as previous research has shown that benzodiazepines may increase the risk of developing or worsening inflammatory conditions, like lung inflammation and inflammatory bowel disease. For years, experts have tried—without much success—to better understand the molecular mechanisms that may be driving these side effects.

Now, a research team led by Virginia Commonwealth University and Columbia University has gained novel insights into a protein suspected to be involved in benzodiazepine-related inflammation. Their findings, published in The Proceedings of the National Academy of Sciences, could inform strategies to improve benzodiazepine drug design as well as open new opportunities for treating inflammation-related conditions, including certain cancers, arthritis, Alzheimer’s disease and multiple sclerosis.

“Numerous attempts have been made to determine the structure and elucidate the function of this mysterious membrane protein family,” said Youzhong Guo, Ph.D., an associate professor in the VCU School of Pharmacy’s Department of Medicinal Chemistry and one of the lead researchers of the new study. “Now, after decades of research, we finally have promising evidence that resolves some of the mysteries around this protein and could be crucial for advancing benzodiazepine drug design.”

Benzodiazepines produce their therapeutic effect by binding with GABAAreceptors in the brain. However, the drug has an equally strong affinity to human mitochondrial tryptophan-rich sensory proteins (HsTSPO1), located on the outer membrane of mitochondria in cells. This type of protein is linked to several neurodegenerative diseases, including Alzheimer’s, and researchers have suspected that HsTSPO1 may be involved in certain side effects of benzodiazepine drugs.

However, both the structure and function of this protein family have been debated within the scientific community, inhibiting efforts to understand its role in disease and develop effective therapeutics. Many scientists have theorized that HsTSPO1’s potential function is to transport cholesterol across membranes to regulate the development of steroid hormones.

But Guo and Wayne Hendrickson, Ph.D., a professor in the Department of Biochemistry and Molecular Biophysics at Columbia’s Vagelos College of Physicians and Surgeons and co-author of the new study, believed that HsTSPO1 is more likely to have a different function.

“Tryptophan-rich sensory proteins like HsTSPO1 are found in all forms of life, from bacteria and plants to animals and humans,” said Guo, who also serves on the research faculty at the VCU Center for Drug Discovery. “We know that this type of protein functions as an enzyme in bacteria, and when you consider evolutionary theory, the same type of protein is likely to be an enzyme in humans as well.”