# Cholinergic anthelmintics: Tachyphylaxis mechanisms and control in a parasitic nematode model,Brugia malayi

> **NIH NIH R21** · CREIGHTON UNIVERSITY · 2024 · $223,622

## Abstract

Project Summary
Soil-transmitted helminth infections are a global concern for public health and affect over 1 billion
people worldwide. Infections caused by Ascaris lumbricoides, Trichuris trichiura (whipworms), and
Ancylostoma duodenale (hookworms) affect people in warm and moist climates often lacking in
hygiene and sanitation and in temperate zones during warmer months. Infected children develop
severe malnutrition and show severe physical and cognitive growth. Control of these parasites
depends on the administration of anthelmintic drugs like benzimidazoles like albendazole,
macrocyclic lactone, ivermectin, and nicotinic agonists like levamisole and pyrantel. The
development of resistance to these anthelmintics poses a great challenge in controlling the
transmission of these diseases. Parasitic nematodes are complex organisms that adopt complex
mechanisms to resist exposure to anthelmintic drugs. We have identified tachyphylaxis as one
mechanism the parasite utilizes to resist and recover motility in the continued exposure to the
cholinergic anthelmintic levamisole. The endoplasmic reticulum retention protein, NRA-2, is one
of the proteins implicated in modulating tachyphylaxis in the female Brugia malayi parasites. The
transcription factor, DAF-12 is upregulated in tachyphylactic worms and could play a key role in
mediating tachyphylaxis. Macrocyclic lactone, abamectin, has limited effect on its own on the
motility of adult B. malayi but, when applied in combination with levamisole, prevents
tachyphylaxis and recovery of motility. Here, we propose,
Aim #1: To test the hypothesis that DAF-12 mediates tachyphylaxis in B. malayi. We will
knockdown daf-12 in adult B. malayi to determine its role in mediating tachyphylaxis. We will
measure transcript levels of nra-2 in daf-12 knockdown worms to determine the role of DAF-12 in
regulating the expression of nra-2. We will also target DAF-12 using agonists to prevent
tachyphylaxis.
Aim #2: To test the hypothesis that muscle calcium concentrations & calcium release
mechanisms produced by levamisole are changed in the presence of macrocyclic
lactones. We will investigate the effects of macrocyclic lactones, abamectin, ivermectin, and
moxidectin in prolonging the paralysis induced by levamisole. We will evaluate the change in
calcium release mechanisms due to macrocyclic lactones by performing RNAi of the ryanodine
and the IP3 receptors, unc-68 and itr-1 in B. malayi, and performing in vivo calcium imaging using
C. elegans.
At the end of these experiments, we will have characterized DAF-12 as a novel anthelmintic target
that could help prevent cholinergic tachyphylaxis. We would have an insight into the effect of
macrocyclic lactones on levamisole calcium release mechanisms in nematode muscle. These
studies will provide an improved mechanistic insight into cholinergic tachyphylaxis and a rational
avenue to prevent worm recovery and resistance.

## Key facts

- **NIH application ID:** 10868740
- **Project number:** 5R21AI173819-03
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Sudhanva Srinivas Kashyap
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $223,622
- **Award type:** 5
- **Project period:** 2023-06-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868740

## Citation

> US National Institutes of Health, RePORTER application 10868740, Cholinergic anthelmintics: Tachyphylaxis mechanisms and control in a parasitic nematode model,Brugia malayi (5R21AI173819-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10868740. Licensed CC0.

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