William J. Sullivan, Jr., Ph.D., assistant professor of pharmacology and toxicology
INDIANAPOLIS — A long-established drug for treating high blood pressure could get new life as a weapon against the parasites responsible for toxoplasmosis and malaria.
Researchers at Indiana University School of Medicine reported that the drug guanabenz was effective against the latent cyst state of the Toxoplasma gondii parasite that takes refuge in the brain and is unaffected by the body’s immune system or existing anti-parasitic drugs.
The Toxoplasma gondii research, published online in the journal Antimicrobial Agents and Chemotherapy, was conducted in mice. But because guanabenz has been approved by U.S. Food and Drug Administration for decades, it could be repurposed quickly as a new way to treat toxoplasmosis, said William J. Sullivan Jr., Ph.D., professor of pharmacology and toxicology at the IU School of Medicine.
An estimated 30-40 percent of the human population is infected by the Toxoplasma gondii parasite. The parasite, which reproduces in cats, is well-known for altering the behavior of infected mice, which lose their fear of cat odors, making them easy prey for cats. The parasite has also gained some notoriety due to speculation that its presence in the brain may alter human behavior.
For most the impact of Toxoplasma infection is minor because the body’s immune system quickly forces the parasite to convert into its inactive cyst state. Among immune-compromised people, however, the parasite can reactivate and cause serious disease.
Dr. Sullivan and colleague Ronald C. Wek, Ph.D., professor of biochemistry and molecular biology, previously identified a key molecular signal that oversees protein production during the parasite’s conversion to the inactive state. Guanabenz interferes with that molecular signaling process.
Testing guanabenz in Toxoplasma-infected mice, post-doctoral scientist Imaan Benmerzouga of the IU School of Medicine found that the drug not only helped mice fight off the replicating stage of infection, but also reduced the number of brain cysts in the animals.
“This finding was a big surprise and a potentially very important discovery. There are few reports of pharmacological agents that have an effect on the latent stage of toxoplasmosis,” Dr. Sullivan said. “Dr. Benmerzouga found a drug that decreases these cysts in mice – that is good news. The fact that this drug is already FDA-approved makes this great news.”
In additional laboratory experiments, collaborating with Michael Ferdig, Ph.D., professor of biological sciences at Notre Dame, the researchers found that guanabenz inhibited the replication of the related parasite responsible for malaria, suggesting that this drug may be active against multiple infectious agents. Studies into the precise mechanism of action for guanabenz against different pathogens are underway.
In addition to Drs. Benmerzouga, Sullivan, Wek and Ferdig, researchers contributing to the study were Lisa A. Checkley of Notre Dame and Gustavo Arrizabalaga of the IU School of Medicine.
The research was supported by National Institutes of Health grants R21 AI105786 and T32 AI060519.