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How do the macrocyclic lactones kill filarial nematode larvae?

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  • Published:
Invertebrate Neuroscience

Abstract

The macrocyclic lactones (MLs) are one of the few classes of drug used in the control of the human filarial infections, onchocerciasis and lymphatic filariasis, and the only one used to prevent heartworm disease in dogs and cats. Despite their importance in preventing filarial diseases, the way in which the MLs work against these parasites is unclear. In vitro measurements of nematode motility have revealed a large discrepancy between the maximum plasma concentrations achieved after drug administration and the amounts required to paralyze worms. Recent evidence has shed new light on the likely functions of the ML target, glutamate-gated chloride channels, in filarial nematodes and supports the hypothesis that the rapid clearance of microfilariae that follows treatment involves the host immune system.

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References

  • Accardi MV, Beech RN, Forrester SG (2012) Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics. Invertebr Neurosci 12:3–12

    Article  CAS  Google Scholar 

  • Adelsberger H, Scheuer T, Dudel J (1997) A patch clamp study of a glutamatergic chloride channel on pharyngeal muscle of the nematode Ascaris suum. Neurosci Lett 230:183–186

    Article  CAS  PubMed  Google Scholar 

  • Al-Azzam SI, Fleckenstein L, Cheng KJ, Dzirnianski MT, McCall JW (2007) Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogs. Biopharm Drug Dispos 28:431–438

    Article  CAS  PubMed  Google Scholar 

  • Alves LC, Brayner FAS, Silva LF, Peixoto CA (2005) The ultrastructure of infective larvae (L3) of Wuchereria bancrofti after treatment with diethylcarbamazine. Micron 36:67–72

    Article  CAS  PubMed  Google Scholar 

  • Anonymous (2005) American Heartworm Society—2005 recommendations for dogs—updated guidelines for diagnosis, prevention, and management. Vet Technician 26:660–667

    Google Scholar 

  • Ashour DS (2013) Trichinella spiralis immunomodulation: an interactive multifactorial process. Exp Rev Clin Immunol 9:669–675

    Article  CAS  Google Scholar 

  • Avery L, Horvitz HR (1990) Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. J Exp Zool 253:263–270

    Article  CAS  PubMed  Google Scholar 

  • Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC (2014) A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoS Negl Trop Dis 8:e0002953

    Article  CAS  Google Scholar 

  • Baraka OZ, Mahmoud BM, Marschke CK, Geary TG, Homeida MMA, Williams JF (1996) Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. Eur J Clin Pharmacol 50(5):407–410

    Article  CAS  PubMed  Google Scholar 

  • Beech RN, Neveu C (2015) The evolution of pentameric ligand-gated ion-channels and the changing family of anthelmintic drug targets. Parasitology 142:303–317

    Article  CAS  PubMed  Google Scholar 

  • Beech R, Levitt N, Cambos M, Zhou SF, Forrester SG (2010a) Association of ion-channel genotype and macrocyclic lactone sensitivity traits in Haemonchus contortus. Mol Biochem Parasitol 171:74–80

    Article  CAS  PubMed  Google Scholar 

  • Beech RN, Wolstenholme AJ, Neveu C, Dent JA (2010b) Nematode parasite genes: what’s in a name? Trends Parasitol 26:334–340

    Article  CAS  PubMed  Google Scholar 

  • Blackhall WJ, Prichard RK, Beech RN (2003) Selection at a gamma-aminobutyric acid receptor gene in Haemonchus contortus resistant to avermectins/milbemycins. Mol Biochem Parasitol 131:137–145

    Article  CAS  PubMed  Google Scholar 

  • Bourguinat C, Keller K, Blagburn B, Schenker R, Geary TG, Prichard RK (2011) Correlation between loss of efficacy of macrocyclic lactone heartworm anthelmintics and P-glycoprotein genotype. Vet Parasitol 176(4):374–381

    Article  CAS  PubMed  Google Scholar 

  • Bourguinat C, Lee ACY, Lizundia R, Blagburn BL, Liotta JL, Kraus MS et al (2015) Macrocyclic lactone resistance in Dirofilaria immitis: failure of heartworm preventives and investigation of genetic markers for resistance. Vet Parasitol 210:167–178

    Article  CAS  PubMed  Google Scholar 

  • Bowman DD, Atkins CE (2009) Heartworm biology, treatment and control. Vet Clin Small Anim 39:1127–1158

    Article  Google Scholar 

  • Bowman DD, Mannella C (2011) Macrocyclic lactones and Dirofilaria immitis microfilariae. Top Companion Anim Med 26:160–172

    Article  PubMed  Google Scholar 

  • Bowman DD, Grazette AR, Basel C, Wang YY, Hostetler JA (2016) Protection of dogs against canine heartworm infection 28 days after four monthly treatments with advantage Multi(R) for dogs. Parasit Vectors 9:12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brownlee DA, Holden-Dye L, Walker RJ (1997) Actions of the anthelmintic ivermectin on the pharyngeal muscle of the parasitic nematode Ascaris suum. Parasitology 115:553–561

    Article  CAS  PubMed  Google Scholar 

  • Buck AH, Coakley G, Simbari F, McSorley HJ, Quintana JF, Le Bihan T et al (2014) Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat Commun 5:6488

    Article  CAS  Google Scholar 

  • Buckingham SD, Sattelle DB (2008) Strategies for automated analysis of C. elegans locomotion. Invertebr Neurosci 8:121–131

    Article  Google Scholar 

  • Buckingham SD, Sattelle DB (2009) Fast, automated measurement of nematode swimming (thrashing) without morphometry. BMC Neurosci 10:84

    Article  PubMed  PubMed Central  Google Scholar 

  • Buckingham SD, Partridge FA, Sattelle DB (2014) Automated, high-throughput, motility analysis in Caenorhabditis elegans and parasitic nematodes: applications in the search for new anthelmintics. Int J Parasitol Drugs Drug Resist 4:226–232

    Article  PubMed  PubMed Central  Google Scholar 

  • Calahorro F, Fereiro T, Morgan H, O’Connor V, Holden-Dye L (2015) Neurochip: a microfluidic device for improved resolution and throughput for chemical screening for crop protection and animal health. J Nematol 47:227–228

    Google Scholar 

  • Canga AG, Prieto AMS, Liebana MJD, Martinez NF, Vega MS, Vieitez JJG (2008) The pharmacokinetics and interactions of ivermectin in humans—a mini-review. Aaps J 10:42–46

    Article  CAS  Google Scholar 

  • Chandrashekar R, Beall MJ, Saucier J, O’Connor T, McCall JW, McCall SD (2014) Experimental Dirofilaria immitis infection in dogs: effects of doxycycline and Advantage Multi(R) administration on immature adult parasites. Vet Parasitol 206:93–98

    Article  CAS  PubMed  Google Scholar 

  • Cheeseman CL, Delany NS, Woods DJ, Wolstenholme AJ (2001) High-affinity ivermectin binding to recombinant subunits of the Haemonchus contortus glutamate-gated chloride channel. Mol Biochem Parasitol 114:161–168

    Article  CAS  PubMed  Google Scholar 

  • Chehayeb JF, Robertson AP, Martin RJ, Geary TG (2014) Proteomic analysis of adult Ascaris suum fluid compartments and secretory products. PLoS Negl Trop Dis 8:0002939

    Article  CAS  Google Scholar 

  • Court JP, Martin-Short M, Lees GM (1986) A comparison of the response of Dipetalonema viteae and Brugia pahangi adult worms to antifilarial agents in vitro. Trop Med Parasitol 37:375–380

    CAS  PubMed  Google Scholar 

  • Cully DF, Vassilatis DK, Liu KK, Paress P, Van der Ploeg LHT, Schaeffer JM, Arena JP (1994) Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371:707–711

    Article  CAS  PubMed  Google Scholar 

  • Cupp EW, Bernardo MJ, Kiszewski AE, Collins RC, Taylor HR, Aziz MA et al (1986) The effects of ivermectin on transmission of Onchocerca volvulus. Science 231:740–742

    Article  CAS  PubMed  Google Scholar 

  • Daurio CP, Cheung EN, Jeffcoat AR, Skelly BJ (1992) Bioavailability of ivermectin administered orally to dogs. Vet Res Commun 16(2):125–130

    Article  CAS  PubMed  Google Scholar 

  • Delany NS, Laughton DL, Wolstenholme AJ (1998) Cloning and localisation of an avermectin receptor-related subunit from Haemonchus contortus. Mol Biochem Parasitol 97:177–187

    Article  CAS  PubMed  Google Scholar 

  • Demeler J, Kuttler U, El-Abdellati A, Stafford K, Rydzik A, Varady M et al (2010) Standardization of the larval migration inhibition test for the detection of resistance to ivermectin in gastro intestinal nematodes of ruminants. Vet Parasitol 174:58–64

    Article  CAS  PubMed  Google Scholar 

  • Dent JA, Davis MW, Avery L (1997) avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. EMBO J 16:5867–5879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dent JA, Smith MM, Vassilatis DK, Avery L (2000) The genetics of ivermectin resistance in Caenorhabditis elegans. Proc Natl Acad Sci USA 97:2674–2679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elkassaby MH (1991) Ivermectin uptake and distribution in the plasma and tissue of sudanese and mexican patients infected with Onchocerca volvulus. Trop Med Parasitol 42:79–81

    CAS  PubMed  Google Scholar 

  • Evans CC, Moorhead AR, Storey BE, Wolstenholme AJ, Kaplan RM (2013) Development of an in vitro bioassay for measuring susceptibility to macrocyclic lactone anthelmintics in Dirofilaria immitis. Int J Parasitol Drugs Drug Resist 3:102–108

    Article  PubMed  PubMed Central  Google Scholar 

  • Geary TG, Sims SM, Thomas EM (1993) Haemonchus contortus: ivermectin-induced paralysis of the pharynx. Exp Parasitol 77:88–96

    Article  CAS  PubMed  Google Scholar 

  • Geary TG, Bourguinat C, Prichard RK (2011) Evidence for macrocyclic lactone anthelmintic resistance in Dirofilaria immitis. Top Companion Anim Med 26:186–192

    Article  PubMed  Google Scholar 

  • Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L (2012) Natural variation in a glutamate-gated chloride channel subunit confers avermectin resistance in C. elegans. Science 335:574–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gokbulut C, Karademir U, Boyacioglu M, McKellar QA (2006) Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs. Vet Parasitol 135:347–354

    Article  CAS  PubMed  Google Scholar 

  • Gunawardena NK, Fujimaki Y, Aoki Y, Mishima N, Ezaki T, Uni S et al (2005) Differential effects of diethylcarbamazine, tetracycline and the combination on Brugia pahangi adult females in vitro. Parasitol Int 54:253–259

    Article  CAS  PubMed  Google Scholar 

  • Hampshire VA (2005) Evaluation of efficacy of heartworm preventive products at the FDA. Vet Parasitol 133:191–195

    Article  PubMed  Google Scholar 

  • Harnett W (2014) Secretory products of helminth parasites as immunomodulators. Mol Biochem Parasitol 195:130–136

    Article  CAS  PubMed  Google Scholar 

  • Harnett W, Harnett MM (2006) Molecular basis of worm-induced immunomodulation. Parasite Immunol 28:535–543

    Article  CAS  PubMed  Google Scholar 

  • Hawking F (1967) The 24-Hour Periodicity of Microfilariae: biological Mechanisms Responsible for Its Production and Control. Proc R Soc Ser B 169:59–76

    Article  Google Scholar 

  • Hayasaki M, Okajima J, Song KH, Shiramizu K (2003) Diurnal variation in microfilaremia in a cat experimentally infected with larvae of Dirofilaria immitis. Vet Parasitol 111:267–271

    Article  CAS  PubMed  Google Scholar 

  • Hibbs RE, Gouaux E (2011) Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474:54–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoerauf A, Satoguina J, Saeftel M, Specht S (2005) Immunomodulation by filarial nematodes. Parasite Immunol 27:417–429

    Article  CAS  PubMed  Google Scholar 

  • Holden-Dye L, Walker RJ (1990) Avermectin and avermectin derivatives are antagonists at the 4-aminobutyric acid (GABA) receptor on the somatic muscle-cells of Ascaris—is this the site of anthelmintic action. Parasitology 101:265–271

    Article  CAS  PubMed  Google Scholar 

  • Horoszok L, Raymond V, Sattelle DB, Wolstenholme AJ (2001) GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans. Br J Pharmacol 132:1247–1254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kass IS, Wang CC, Walrond JP, Stretton AOW (1980) Avermectin B1A, a paralysing anthelmintic that affects interneurones and inhibitory motor neurones in Ascaris. Proc Natl Acad Sci USA 77:6211–6215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kotze AC, Le Jambre LF, O’Grady J (2006) A modified larval migration assay for detection of resistance to macrocyclic lactones in Haemonchus contortus, and drug screening with Trichostrongylidae parasites. Vet Parasitol 137:294–305

    Article  CAS  PubMed  Google Scholar 

  • Kotze AC, Hines BM, Ruffell AP (2012) A reappraisal of the relative sensitivity of nematode pharyngeal and somatic musculature to macrocylic lactone drugs. Int J Parasitol Drugs Drug Resist 2:29–35

    Article  PubMed  CAS  Google Scholar 

  • Krause RM, Buisson B, Bertrand S, Corringer PJ, Galzi JL, Changeux JP, Bertrand D (1998) Ivermectin: a positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 53:283–294

    CAS  PubMed  Google Scholar 

  • Lallemand E, Lespine A, Alvinerie M, Bousquet-Melou A, Toutain PL (2007) Estimation of absolute oral bioavailability of moxidectin in dogs using a semi-simultaneous method: influence of lipid co-administration. J Vet Pharmacol Ther 30:375–380

    Article  CAS  PubMed  Google Scholar 

  • Lammie PJ, Hightower AW, Eberhard ML (1994) Age-specific prevalence of antigenemia in a Wuchereria bancrofti-exposed population. Am J Trop Med Hyg 51:348–355

    CAS  PubMed  Google Scholar 

  • Laughton DL, Lunt GG, Wolstenholme AJ (1997) Reporter gene constructs suggest the Caenorhabditis elegans avermectin receptor β-subunit is expressed solely in the pharynx. J Exp Biol 200:1509–1514

    CAS  PubMed  Google Scholar 

  • Li BW, Rush AC, Weil GJ (2014) High level expression of a glutamate-gated chloride channel gene in reproductive tissues of Brugia malayi may explain the sterilizing effect of ivermectin on filarial worms. Int J Parasitol Drugs Drug Resist 4:71–76

    Article  PubMed  PubMed Central  Google Scholar 

  • Maizels RM, Denham DA (1992) Diethylcarbamazine (DEC)—immunopharmacological interactions of an anti-filarial drug. Parasitology 105:S49–S60

    Article  PubMed  Google Scholar 

  • Marcellino C, Gut J, Lim KC, Singh R, McKerrow J, Sakanari J (2012) Wormassay: a novel computer application for whole-plate motion-based screening of macroscopic parasites. PLoS Negl Trop Dis 6:e1494

    Article  PubMed  PubMed Central  Google Scholar 

  • Martin RJ (1996) An electrophysiological preparation of Ascaris suum pharyngeal muscle reveals a glutamate-gated chloride channel sensitive to the avermectin analogue, milbemycin D. Parasitology 112:247–252

    Article  CAS  PubMed  Google Scholar 

  • McArthur CL, Handel IG, Robinson A, Hodgkinson JE, Bronsvoort BM, Burden F et al (2015) Development of the larval migration inhibition test for comparative analysis of ivermectin sensitivity in cyathostomin populations. Vet Parasitol 212:292–298

    Article  CAS  PubMed  Google Scholar 

  • McCavera S, Rogers AT, Yates DM, Woods DJ, Wolstenholme AJ (2009) An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode, Haemonchus contortus. Mol Pharmacol 75:1347–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKellar QA, Gokbulut C (2012) Pharmacokinetic features of the antiparasitic macrocyclic lactones. Curr Pharm Biotechnol 13:888–911

    Article  CAS  PubMed  Google Scholar 

  • McSorley HJ, Hewitson JP, Maizels RM (2013) Immunomodulation by helminth parasites: defining mechanisms and mediators. Int J Parasitol 43:301–310

    Article  CAS  PubMed  Google Scholar 

  • Molyneux DH, Zagaria N (2002) Lymphatic filariasis elimination: progress in global programme development. Ann Trop Med Parasitol 96:S15–S40

    Article  PubMed  Google Scholar 

  • Moreno Y, Nabhan JF, Solomon J, Mackenzie CD, Geary TG (2010) Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi. Proc Natl Acad Sci USA 107:20120–20125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nelson FK, Riddle DL (1984) Functional-study of the Caenorhabditis elegans secretory-excretory system using laser microsurgery. J Exp Zool 231:45–56

    Article  CAS  PubMed  Google Scholar 

  • Nelson FK, Albert PS, Riddle DL (1983) Fine structure of the Caenorhabditis elegans secretory excretory system. J Ultrastruct Res 82:156–171

    Article  CAS  PubMed  Google Scholar 

  • Njoo FL, Hack CE, Oosting J, Stilma JS, Kijlstra A (1993) Neutrophil activation in ivermectin-treated onchocerciasis patients. Clin Exp Immunol 94:330–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Njoo FL, Hack CE, Oosting J, Luyendijk L, Stilma JS, Kijlstra A (1994) C-reactive protein and interleukin-6 are elevated in onchocerciasis patients after ivermectin treatment. J Infect Dis 170:663–668

    Article  CAS  PubMed  Google Scholar 

  • Nolan TJ, Lok JB (2012) Macrocyclic lactones in the treatment and control of parasitism in small companion animals. Curr Pharm Biotechnol 13:1078–1094

    Article  CAS  PubMed  Google Scholar 

  • Osei-Atweneboana MY, Awadzi K, Attah SK, Boakye DA, Gyapong JO, Prichard RK (2011) Phenotypic evidence of emerging ivermectin resistance in Onchocerca volvulus. PLoS Negl Trop Dis 5:e998

    Article  PubMed  PubMed Central  Google Scholar 

  • Ottesen EA (2006) Lymphatic filariasis: treatment, control and elimination. In: Molyneux DH (ed) Advances in parasitology, vol 61: control of human parasitic diseases (vol 61, advances in parasitology). San Diego: Elsevier Academic Press Inc, pp 395–441

  • Ottesen EA, Vijayasekaran V, Kumaraswami V, Pillai SVP, Sadanandam A, Frederick S et al (1990) A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis. New Engl J Med 322:1113–1117

    Article  CAS  PubMed  Google Scholar 

  • Pemberton DJ, Franks CJ, Walker RJ, Holden-Dye L (2001) Characterization of glutamate-gated chloride channels in the pharynx of wild-Type and mutant Caenorhabditis elegans delineates the role of the subunit GluCl-α 2 in the function of the native receptor. Mol Pharmacol 59:1037–1043

    CAS  PubMed  Google Scholar 

  • Pineda MA, Lumb F, Harnett MM, Harnett W (2014) ES-62, a therapeutic anti-inflammatory agent evolved by the filarial nematode Acanthocheilonema viteae. Mol Biochem Parasitol 194:1–8

    Article  CAS  PubMed  Google Scholar 

  • Portillo V, Jagannathan S, Wolstenholme AJ (2003) Distribution of glutamate-gated chloride channel subunits in the parasitic nematode Haemonchus contortus. J Comp Neurol 462:213–222

    Article  CAS  PubMed  Google Scholar 

  • Pulaski CN, Malone JB, Bourguinat C, Prichard R, Geary T, Ward D, Klei TR, Guidry T, Smith GB, Delcambre B, Bova J, Pepping J, Carmichael J, Schenker R, Pariaut R (2014) Establishment of macrocylic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. Parasites Vectors 7:494

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rao UR, Chandrashekar R, Subrahmanyam D (1987) Effect of ivermectin on serum dependent cellular interactions to Dipetalonema viteae microfilariae. Trop Med Parasitol 38:123–127

    CAS  PubMed  Google Scholar 

  • Rao VTS, Siddiqui SZ, Prichard RK, Forrester SG (2009) A dopamine-gated ion channel (HcGGR3*) from Haemonchus contortus is expressed in the cervical papillae and is associated with macrocyclic lactone resistance. Mol Biochem Parasitol 166:54–61

    Article  CAS  PubMed  Google Scholar 

  • Raza A, Kopp SR, Jabbar A, Kotze AC (2015) Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro. Vet Parasitol 211:80–88

    Article  CAS  PubMed  Google Scholar 

  • Schulzkey H, Greene BM, Awadzi K, Lariviere M, Klager S, Dadzie Y et al (1986) Efficacy of ivermectin on the reproductivity of female Onchocerca volvulus. Trop Med Parasitol 37:89

    Google Scholar 

  • Seketeli A, Adeoye G, Eyamba A, Nnoruka E, Drameh P, Amazigo UV et al (2002) The achievements and challenges of the African Programme for Onchocerciasis Control (APOC). Ann Trop Med Parasitol 96:15–28

    Article  Google Scholar 

  • Serrano-Saiz E, Poole RJ, Felton T, Zhang FF, De La Cruz ED, Hobert O (2013) Modular control of glutamatergic neuronal identity in C. elegans by distinct homeodomain proteins. Cell 155:659–673

    Article  CAS  PubMed  Google Scholar 

  • Shan Q, Haddrill JL, Lynch JW (2001) Ivermectin, an unconventional agonist of the glycine receptor chloride channel. J Biol Chem 276:12556–12564

    Article  CAS  PubMed  Google Scholar 

  • Sheriff JC, Kotze AC, Sangster NC, Hennessy DR (2005) Effect of ivermectin on feeding by Haemonchus contortus in vivo. Vet Parasitol 128:341–346

    Article  CAS  PubMed  Google Scholar 

  • Silberberg SD, Li MF, Swartz KJ (2007) Ivermectin interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels. Neuron 54:263–274

    Article  CAS  PubMed  Google Scholar 

  • Smout MJ, Kotze AC, McCarthy JS, Loukas A (2010) A novel high throughput assay for anthelmintic drug screening and resistance diagnosis by real-time monitoring of parasite motility. PLoS Negl Trop Dis 4:e885

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Storey B, Marcellino C, Miller M, Maclean M, Mostafa E, Howell S et al (2014) Utilization of computer processed high definition video imaging for measuring motility of microscopic nematode stages on a quantitative scale: “The Worminator’’. Int J Parasitol Drugs Drug Resist 4:233–243

    Article  PubMed  PubMed Central  Google Scholar 

  • Tompkins JB, Stitt LE, Ardelli BF (2010) Brugia malayi: in vitro effects of ivermectin and moxidectin on adults and microfilariae. Exp Parasitol 124:394–402

    Article  CAS  PubMed  Google Scholar 

  • Vassilatis DK, Arena JP, Plasterk RHA, Wilkinson H, Schaeffer JM, Cully DF et al (1997) Genetic and biochemical evidence for a novel avermectin sensitive chloride channel in C. elegans isolation and characterisation. J Biol Chem 272:33167–33174

    Article  CAS  PubMed  Google Scholar 

  • Vatta AF, Dzimianski M, Storey BE, Camus MS, Moorhead AR, Kaplan RM et al (2014) Ivermectin-dependent attachment of neutrophils and peripheral blood mononuclear cells to Dirofilaria immitis microfilariae in vitro. Vet Parasitol 206:38–42

    Article  CAS  PubMed  Google Scholar 

  • Vickery AC, Nayar JK, Tamplin ML (1985) Diethylcarbamazine-mediated clearance of Brugia pahangi microfilariae in immunodeficient nude-mice. Am J Trop Med Hyg 34:476–483

    CAS  PubMed  Google Scholar 

  • Wagland BM, Jones WO, Hribar L, Bendixsen T, Emery DL (1992) A new simplified assay for larval migration-inhibition. Int J Parasitol 22:1183–1185

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Wang S, Zhang H, Yuan C, Yan RF, Song XK et al (2014) Galectin Hco-gal-m from Haemonchus contortus modulates goat monocytes and T cell function in different patterns. Parasit Vectors 7:342

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wharton DA, Sommerville RI (1984) The structure of the excretory system of the infective larva of Haemonchus contortus. Int J Parasitol 14:591–600

    Article  CAS  PubMed  Google Scholar 

  • Williamson SM, Walsh TK, Wolstenholme AJ (2007) The cys-loop ligand-gated ion channel gene family of Brugia malayi and Trichinella spiralis: a comparison with Caenorhabditis elegans. Invertebr Neurosci 7:219–226

    Article  CAS  Google Scholar 

  • Wolstenholme AJ (2012) Glutamate-gated chloride channels. J Biol Chem 287:40232–40238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolstenholme AJ, Rogers AT (2005) Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology 131:S85–S95

    Article  CAS  PubMed  Google Scholar 

  • Wolstenholme AJ, Evans CC, Jimenez PD, Moorhead AR (2015) The emergence of macrocyclic lactone resistance in the canine heartworm, Dirofilaria immitis. Parasitology 142:1249–1259

    Article  CAS  PubMed  Google Scholar 

  • Yates DM, Wolstenholme AJ (2004) An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis. Int J Parasitol 34:1075–1081

    Article  CAS  PubMed  Google Scholar 

  • Zahner H, Schmidtchen D, Mutasa JA (1997) Ivermectin-induced killing of microfilariae in vitro by neutrophils mediated by NO. Exp Parasitol 86:110–117

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We should look to thank Ray Kaplan, Balazs Rada and Andrew Moorhead for endless stimulating discussions and for all the help and reagents they and their groups have supplied. The parasites used in the authors’ laboratory were supplied by the NIH Filarial Research Resource Center. Research in the authors’ laboratory is supported by award R01AI103140 from the National Institutes of Health.

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  1. Ruby Coates

    Present address: Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK

  2. Ciaran J. McCoy

    Present address: School of Biological Sciences, Medical Biology Centre, Queen’s University, 97 Lisburn Road, Belfast, BT9 7BL, UK

Authors and Affiliations

  1. Department of Infectious Diseases and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, 30602, USA

    Adrian J. Wolstenholme, Mary J. Maclean, Ruby Coates, Ciaran J. McCoy & Barbara J. Reaves

  2. Department of Infectious Diseases, College of Veterinary Medicine, 501 D. W. Brooks Drive, Athens, GA, 30602, USA

    Adrian J. Wolstenholme

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Wolstenholme, A.J., Maclean, M.J., Coates, R. et al. How do the macrocyclic lactones kill filarial nematode larvae?. Invert Neurosci 16, 7 (2016). https://doi.org/10.1007/s10158-016-0190-7

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  • DOI: https://doi.org/10.1007/s10158-016-0190-7

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