Abstract
The anthelmintic activity of the avermectins was first described in 1979 (Burg et al. 1979; Egerton et al. 1979; Miller et al. 1979). The mode of action of these compounds, however, has remained elusive. Identifying the mode of action is all the more difficult because the avermectins have been studied in so many different model systems with an array of experimental protocols. For example, direct injection of avermectin (AVM) into Ascaris suum results in a rapid paralysis that is neither flaccid nor rigid; incubation of the free living nematode, Caenorhabditis elegans, with AVM results in slow-onset rigid paralysis; and incubation of Haemonchous contortus ex vivo with AVM has no observable effect. Exactly why AVM affects these 3 AVM-sensitive nematodes differently is unknown, but it may reflect in part the drug’s ability to reach its site of action. The problems in identifying the mechanism(s) by which the avermectins work have been further confounded by several additional factors: the drug acts at multiple sites; various target species have different sensitivities to the drug; and avermectins have poor solubility in aqueous solutions.
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References
Abalis IM, Eldefrawi AT (1986) [3H]Muscimol binding to a putative GABA receptor in honey bee brain and its interaction with avermectin B1a. Pestic. Biochem. Physiol 25:279–287
Albert J, Lingle DH, Marder E, O’Neil MB (1986) A GABA-activated chloride- conductance not blocked by picrotoxin on spiny lobster neuromuscular preparations. Brit. J. Pharmacol 87:771–779
Burg RW, Miller BM, Baker EE, Birnbaum J, Currie JA, Harman R, Kong VL, Monaghan RL, Olson G, Putter I, Tunac JP, Wallick H, Stapley EO, Oiwa R, Omura S (1979) The action of avermectin on identified central neurons from Helix and its interaction with acetylcholine and gamma-aminobutyric acid responses. Antimicrob. Agents Chemother. 15:361–367
Calcott PH, Fatig RO (1984a) Inhibition of chitin metabolism by avermectin in susceptible organisms. J. Antibiot. 37:253–259
Calcott PH, Fatig RO (1984b) Avermectin modulation of gamma-aminobutyric acid binding to membranes of rat brain, brine shrimp and a fungus, mucor miehei. J. Antibiot. 37:797–801
Drexler G, Sieghart W (1984a) Properties of high affinity binding site for tritium-labeled avermectin B1a. Eur. J. Pharmacol 99:269–277
Drexler G. Sieghart W (1984b) Evidence for association of a high affinity avermectin binding site with benzodiazepine receptor. Eur. J. Pharmacol 101:201–207
Drexler G. Sieghart W (1984c) Sulfur-35-labeled tert-butyl-bicyclophosphorothionate and avermectin bind to different sites associated with the gamma- aminobutyric acid-benzodiazepine receptor complex. Neurosci. Let. 50: 273–277
Duce IR, Scott RH (1983) GABA sensitivity in the distal bundles of the locust extensor tibiae muscle. J. Physiol. 343:32P
Duce IR, Scott RH (1985) Actions of dihydroavermectin B1a on insect muscle. Brit. J. Pharmacol 85:395–401
Egerton JR, Ostlind DA, Blair LS, Eary DH, Suhayda D, Cifelli S, Riek RF, Campbell WC (1979) Avermectins, new family of potent anthelmintic agents: efficacy of the B1a component. Antimicrob. Agents Chemother. 15:372–378
Ellis C, Nathwani B, Morrice N, Parker P, Evans FJ, Aitken A (1987) Ivermectin: an inhibitor of protein kinase C-: A potential target enzyme for onchocerciases chemotherapy. Brit. J. Pharmacol 91:22P
Fritz LC, Wang CC, Gorio A (1979) Avermectin B1a irreversibly blocks presynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Proc. Natl. Acad. Sci. USA 76:2062–2066
Gordnier PM, Brezner J, Tanenbaum, SW (1987) Chitin metabolism: not a target of avermectin/milbemycin activity in insects. J. Antibiot. 40:110–112
Graham D, Pfeiffer F, Betz H (1982) Avermectin B1a inhibits the binding of strychnine to the glycine receptor of rat spinal cord. Neurosci. Let. 29:173–176
Guidotti A, Tottano G, Costa, E (1978) An endogenous protein modulates the affinity of GABA and benzodiazepine receptors in rat brain. Nature 275:553–555
Harris RA, Allen AM (1985) Functional coupling of GABA receptors to chloride channels in brain membranes. Science 228:1108–1110.
Huang L, Burg R (1986) The avermectin receptor of the American cockroach. Soc. Neurosci. Abstr. #9.9
Ishiko J, Inagake C, Takaori S (1985) Effects of avermectin B1a and picrotoxin on striatal release of dopamine with reference to replacement of extracellular chloride with nitrate. Neuropharm. 24:1147–1154
Kass IS, Stretton AOW, Wand CC (1984) The effects of avermectin and drugs related to acetylcholine and 4-aminobutyric acid on neurotransmission in Ascaris suum. Molec. & Biochem. Parasit. 13:213–225
Kass IS, Wang CC, Walrond JP, Stretton AOW (1980) Avermectin B1a, a paralyzing anthelmintic that affects interneurons and inhibitory motoneurons in Ascaris. Proc. Natl. Acad. Sci. USA 77:6211–6215
Lummis CR, Sattelle DB (1985) GABA and benzodiazepine binding sites in insect CNS. Pestic. Sci. 16:61–65.
Martin R, Pennington AJ (1988) Effect of dihydroavermectin B1a on CI single- channel currents in Ascaris muscle. Neurotox. ’88 Abstr. 141
Meiners BA, Salama AI (1982) Enhancement of benzodiazepine and GABA binding by the novel anxiolytic, tracazolate. Euro. J. Pharmacol. 78:315–322
Mellin TN, Busch RD, Wang CC (1983) Postsynaptic inhibition of invertebrate neuromuscular transmission by avermectin B1a. Neuropharm. 22:89–96
Miller TW, Chaiet L, Cole DJ, Flor JE, Goegelman RT, Gullo VP, Joshua H, Kempf AJ, Krellwitz WR, Monaghan RL, Ormond RE, Wilson KE, Albers-Schonberg G, Putter I (1979) Avermectins, a new family of potent anthelmintic agents: isolation and chromatographic properties. Antimicrob. Agents Chemother. 15:368–371
Nicholson R, Robinson PS, Palmer PJ, Casida JE (1988) Ivermectin-stimulated release of neurotransmitter in the insect central nervous system: modulation by external chloride and inhibition by a novel trioxabicyclooctane and two polychlorocyloalkane insecticides. Neurotox ’88 Abstr. #96
Olsen RW, Snowman AM (1985) Avermectin B1a modulation of gamma- aminobutyric acid-benzodiazepine receptor binding in mammalian brain. J. Neurochem. 44:1074–1082
Onishi JC, Miller TW (1985) The lack of antifungal activity by avermectin B1a Antibiot. 38:1568–1572
Paul SM, Skolnick P, Zatz M (1980) Avermectin B1a: an irreversible activator of the gamma-aminobutyric acid-benzodiazepine-chloride-ionophore receptor complex. Biochem. Biophys. Res. Commun. 96:632–638
Pong S-S, DeHaven R, Wang CC (1981) Stimulation of benzodiazepine binding to rat brain membranes and solubized receptor complex by avermectin B1a and GABA. Biochem. Biophys. Acta 646:143–149
Pong S-S, Wang CC (1982) Avermectin B1a modulation of gamma-aminobutyric acid receptors in rat brain membranes. J. Neurochem. 38:375–379
Pong S-S, Wang CC, Fritz LC (1980) Studies on the mechanism of action of avermectin B1a: stimulation of release of gamma-aminobutyric acid from brain synaptosomes. J. Neurochem. 34:351–358
Sani BP, Vaid A (1988) Specific interaction of ivermectin with retinol-binding protein from filarial parasites. Biochem. J. 249:929–932
Schaeffer JM, Bergstrom AR (1988) Identification of gamma-aminobutyric acid binding sites in Caenorhabditis elegans. Life Sci. 43:1701–1706
Schaeffer JM, Bergstrom AR (in press) The effect of ivermectin on chloride uptake by rat brain synaptosomes. Biochem. Biophys. Res. Comm.
Schaeffer JM, Haines H (in press) Avermectin binding in Caenorhabditis elegans: a two-state model for the avermectin binding site. Biochem. Pharm.
Schwartz RD, Sudak PD, Paul SM (1986) GABA- and barbituate-mediated chloride uptake in rat brain synaptoneurosomes: Evidence for a rapid desensiti- zation of the GABA receptor-coupled chloride ion channel. Molec. Pharm. 30:419–426
Sieghart W, Eichinger A, Riederer P, Jellinger K (1985) Comparison of benzodiazepine receptor binding in membranes from human or rat brain. Neuropharm. 24:751–760
Sigel E, Baur R (1987) Effect of avermectin B1a on chick neuronal gamma- aminobutyric acid receptor channels expressed in Xenopus oocytes. Molec. Pharm. 32:749–752
Soderlaud DM, Adams PM, Bloomquist JR (1987) Differences in the action of avermectin B1a on the GABAA receptor complex of mouse and rat. Biochem. Biophys. Res. Commun. 146:692–698
Stretton AOW, Fishpool RM, Southgate E, Donmoyer JE, Walrond JP, Moses JER, Kass IS (1978) Structure and physiological activity of the motorneurons of the nematode Ascaris. Proc. Natl. Acad. Sci. USA 75:3493–3497
Supavilai P, Karobath M (1981) In vitro modulation by avermectin B1a of the GABA/benzodiazepine receptor complex or fat cerebellum. J. Neurochem. 36:798–805
Tanaka K, Matsumura F (1985) Action of avermectin B1a on the leg muscles and nervous system of the American cockroach. Pest. Biochem. Physiol. 24:124–135
Williams M, Risley EA (1982) Interaction of avermectins with [3H]β-carboline-3 carboxylate ethyl ester and [3H] diazepam binding sites in rat brain cortical membranes. Eur. J. Pharmacol. 77:307–312
Williams M, Risley EA (1984) Ivermectin interactions with benzodiazepine receptors in rat cortex and cerebellum in vitro. J. Neurochem. 42:745–753
Williams M, Yarbrough GG (1979) Enhancement of in vitro binding and some of the pharmacological properties of diazepam by a novel anthelmintic agent, avermectin B1a. Eur. J. Pharmacol. 56:1273–276
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Turner, M.J., Schaeffer, J.M. (1989). Mode of Action of Ivermectin. In: Campbell, W.C. (eds) Ivermectin and Abamectin. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-3626-9_5
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DOI: https://doi.org/10.1007/978-1-4612-3626-9_5
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