Folia Parasitologica 61[6] 561-570 (2014) | DOI: 10.14411/fp.2014.068

Moxidectin causes adult worm mortality of human lymphatic filarial parasite Brugia malayi in rodent models

Meenakshi Verma^1,2, Manisha Pathak¹, Mohd Shahab^1,2, Kavita Singh³, Kalyan Mitra^2,3, Shailja Misra-Bhattacharya^1,2

¹ Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttarpradesh, India;

² Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India;

³ Electron Microscopy Unit, CSIR-Central Drug Research Institute, Lucknow, Uttarpradesh, India

Moxidectin is a macrocyclic lactone belonging to milbemycin family closely related to ivermectin and is currently progressing towards Phase III clinical trial against human infection with the filaria Onchocerca volvulus (Leuckart, 1894). There is a single report on the microfilaricidal and embryostatic activity of moxidectin in case of the human lymphatic filarial parasite Brugia malayi (Brug, 1927) in Mastomys coucha (Smith) but without any adulticidal action. In the present study, the in vitro and in vivo antifilarial efficacy of moxidectin was evaluated on, B. malayi. In vitro moxidectin showed 100% reduction in adult female worm motility at 0.6 µM concentration within 7 days with 68% inhibition in the reduction of MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye) (which is used to detect viability of worms). A 50% inhibitory concentration (IC50) of moxidectin for adult female parasite was 0.242 µM, for male worm 0.186 µM and for microfilaria IC50 was 0.813 µM. In adult B. malayi-transplanted primary screening model (Meriones unguiculatus Milne-Edwards), moxidectin at a single optimal dose of 20 mg/kg by oral and subcutaneous route was found effective on both adult parasites and microfilariae. In secondary screening (M. coucha, subcutaneously inoculated with infective larvae), moxidectin at the same dose by subcutaneous route brought about death of 49% of adult worms besides causing sterilisation in 54% of the recovered live female worms. The treated animals exhibited a continuous and sustained reduction in peripheral blood microfilaraemia throughout the observation period of 90 days. The mechanism of action of moxidectin is suggested to be similar to avermectins. The in silico studies were also designed to explore the interaction of moxidectin with glutamate-gated chloride channels of B. malayi. The docking results revealed a close interaction of moxidectin with various GluCl ligand sites of B. malayi.

Keywords: Nematode, chemotherapy, macrocyclic lactone, jirds, mastomys, microfilaricidal, macrofilaricidal

Received: April 27, 2014; Accepted: July 21, 2014; Prepublished online: November 24, 2014; Published: December 4, 2014  Show citation