Neglected tropical diseases (NTD) threaten billions of the world’s populations that live in endemic regions. For instance, parasitic worms that cause lymphatic filariasis infect just shy of 68 million people across 52 countries, threatening another 882 million. While medications for NTD can always be improved, thankfully, there are some that have been effective for a number of years. However, for many older medications, the method of action is either unknown or has been in dispute. Researchers at the Iowa State University’s College of Veterinary Medicine are looking to set the record straight when it comes to a commonly prescribed drug— diethylcarbamazine (DEC)—in the treatment of lymphatic filariasis, also known as elephantiasis.
Findings from the new study—published recently in Current Biology through an article entitled “Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi”— shows how DEC paralyzes the parasitic worms upending the widely held belief that the medication bolsters a patient’s immune system but doesn’t target the parasites directly. The researchers believe this new data could pave the way to better predict how resistance to the medication may develop in the parasites and allow medical professionals to understand how the medication may interact with other therapies.
DEC was discovered in 1947 and is used to treat a range of diseases caused by parasitic roundworms. The researchers said the scientific consensus for most of the medication’s existence suggested the therapy provoked a response in the host’s immune system to which the parasites are susceptible. But the Iowa scientists wanted to find out if there might be other factors influencing the efficacy of the medication.
“It’s a drug that’s not been extensively worked on for quite a number of years,” noted senior study investigator Richard Martin, PhD, professor of biomedical sciences at Iowa State University’s College of Veterinary Medicine. “People have just left it alone and assume that’s how it works.”
The new study indicates DEC directly targets the parasites with temporary paralysis. The paralysis results when the medication causes pores, called transient receptor potential ion-channels, in the parasites’ cellular membranes to open, allowing calcium to enter. The calcium triggers a retraction in the parasites’ muscle cells, leading to paralysis. This paralysis allows the host’s body to flush the parasites out of the lymphatic system.
“We showed that low concentrations of diethylcarbamazine have direct and rapid (<30 s) temporary spastic paralyzing effects on the parasites that lasts around 4 h, which is produced by diethylcarbamazine opening Transient Receptor Potential (TRP) channels in muscle of Brugia malayi involving TRP-2 (TRPC-like channel subunits),” the authors wrote. “GON-2 and CED-11, TRPM-like channel subunits, also contributed to diethylcarbamazine responses. Opening of these TRP channels produces contraction and subsequent activation of calcium-dependent SLO-1K channels. Recovery from the temporary paralysis is consistent with inactivation of TRP channels.”
“The parasites get displaced out of their local environment and end up getting stuck in liver cells, and then they get gobbled up by the immune system,” Martin added. “So the medication means the parasites are not able to stay in the place they want to.”
Martin explained that previous studies might have missed this paralysis effect because it lasts for only a few hours, maybe four or five before it wears off, and the parasites resume their normal level of activity. The research team used computer-aided video tracking to monitor parasites exposed to diethylcarbamazine. They also measured electrical currents passing through muscle cells and used gene knock-down technology to analyze how the medication affects parasitic activity, he said.
A better understanding of how diethylcarbamazine works will allow doctors to anticipate how parasites might develop resistance to the therapy, Martin said. In addition, the new data could allow doctors to use diethylcarbamazine in concert with other therapies to lead to better outcomes for patients.
“If you know how this therapy works, you can start to select and develop better drugs that are maybe even more potent,” Martin concluded.
