Comparison of electrophysiological and motility assays to study anthelmintic effects in Caenorhabditis elegans. (August 2021)

• Record Type: Journal Article
• Authors: Hahnel, Steffen R.; Roberts, William M.; Heisler, Iring; Kulke, Daniel; Weeks, Janis C.
• Is Part Of: International journal for parasitology. Volume 16(2021)
• Page Start: 174
• Page End: 187
• Publication Date: 2021-08
• Subjects: Caenorhabditis elegans -- Nematode pharynx -- Electropharyngeogram (EPG) -- 8-channel chip -- ScreenChip -- wMicroTracker -- Macrocyclic lactones -- Levamisole -- Pharyngeal pumping -- Anthelmintics; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2021.05.005
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Currently, only a few chemical drug classes are available to control the global burden of nematode infections in humans and animals. Most of these drugs exert their anthelmintic activity by interacting with proteins such as ion channels, and the nematode neuromuscular system remains a promising target for novel intervention strategies. Many commonly-used phenotypic readouts such as motility provide only indirect insight into neuromuscular function and the site(s) of action of chemical compounds. Electrophysiological recordings provide more specific information but are typically technically challenging and lack high throughput for drug discovery. Because drug discovery relies strongly on the evaluation and ranking of drug candidates, including closely related chemical derivatives, precise assays and assay combinations are needed for capturing and distinguishing subtle drug effects. Past studies show that nematode motility and pharyngeal pumping (feeding) are inhibited by most anthelmintic drugs. Here we compare two microfluidic devices ("chips") that record electrophysiological signals from the nematode pharynx (electropharyngeograms; EPGs) ─ the ScreenChip™ and the 8-channel EPG platform ─ to evaluate their respective utility for anthelmintic research. We additionally compared EPG data with whole-worm motility measurements obtained with the wMicroTracker instrument. As references, we used three macrocyclic lactones (ivermectin, moxidectin, and milbemycin oxime), and levamisole, which act on different ion channels. Drug potencies (IC50 and IC95 values) from concentration-response curves, and the time-course of drug effects, were compared across platforms and across drugs. Drug effects on pump timing and EPG waveforms were also investigated. These experiments confirmed drug-class specific effects of the tested anthelmintics and illustrated the relative strengths and limitations of the different assays for anthelmintic research. Graphical abstract: Image 1 Highlights: Anthelmintic drugs inhibit pharyngeal pumping and motility in C. elegans . Two electrophysiological assays and one motility assay were compared. Macrocyclic lactones and levamisole have drug-class-specific effects. A combination of assays most fully reveals anthelmintic effects. Strengths and limitations of the three assays were identified.