Avermectin B1a, a paralyzing anthelmintic that affects interneurons and inhibitory motoneurons in Ascaris.

Abstract

ABSIRACrAvermectin B1. (AVM) is an antiparasitic agent that paralyzes nematodes without causing hypercontraction or flaccid paralysis. Using selective stimulation techniques, we have shown that AVM blocks transmission between interneuron(s) and excitatory motoneurons in the ventral nerve cord of Ascaris. It also inhibits transmission between inhibitory motoneurons and muscle but has little effect on excitatory neuromuscular transmission. Picrotoxin can reverse the AVM-induced block of interneuron-excitatory motoneuron transmission but has no effect on the inhibitory motoneuronal synapse in either the presence or absence of AVM. Our results provide an explanation of how AVM may cause paralysis of nematodes.Avermectin Bia (AVM) is a macrocyclic lactone derived from the mycelia of Streptomyces avermilitis (1-3). It is a potent broad-spectrum anthelmintic and insecticidal agent (4, 5) but has no demonstrated antibacterial or antifungal activity (2).When applied to the neuromuscular junctions of lobster walking legs, the drug rapidly eliminated the inhibitory postsynaptic potentials and then more slowly brought about a reduction in the amplitude of excitatory postsynaptic potentials (6). The input resistance of the muscle fibers also decreased, with a time course similar to that of the reduction of excitatory potentials (6). None of these effects was reversible by washing, but the reductions in the excitatory potentials and input resistance were reversed by picrotoxin. It was postulated that, at the lobster neuromuscular junction, AVM acts to open the chloride channels (6). This could be accomplished by AVM directly or by an AVM-stimulated release of y-aminobutyric acid (GABA) from the inhibitory neuron. AVM has been shown to cause release of GABA from mammalian synaptosomes (7). In binding studies using mammalian brain tissue, no competition was seen between AVM and GABA, showing that, at least in mammals, AVM and GABA do not interact with identical binding sites (8).In the present studies we investigated the mechanism of action of AVM on nematodes. Both the large parasitic nematode Ascaris and the small free-living nematode Caenorhabditis were used for behavioral studies. Electrophysiogical studies were carried out on Ascaris. The effects of AVM were tested in dissected preparations in which single excitatory or inhibitory motoneurons were activated, either directly by electrical stimulation or indirectly by stimulating interneurons that synapse onto the excitatory motoneurons. We find that AVM inhibits transmission between interneurons and excitatory motoneurons. It also inhibits transmission between inhibitory motoneurons and muscle but has little effect on excitatory neuromuscular transmission. The effect of AVM on the interneuron-to-excitatory motoneuron pathway was reversed byThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 6211picrotoxin, but the ac...

Actions of dihydroavermectin B1α on insect muscle

“…One of the major components of the AVM complex is AVM Bla which has been found to have broad spectrum anthelminthic and insecticidal properties (Egerton et al, 1979;Ostlind et al, 1979). AVM Bla has been shown to block neurotransmission at inhibitory neuromuscular synapses and in the ventral nerve cord ofthe nematode Ascaris suum (Kass et al, 1980). Investigations of AVM at the excitatory neuromuscular junction ofinsects have been restricted to the demonstration that AVM does not affect excitatory postsynaptic potentials in cockroach (Periplaneta americana) muscle (Mellin et al, 1983).…”

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

“…In vitro, IVM effects on mf appear only at concentrations far above levels achieved during therapy for filariases (9). In the model nematode Caenorhabditis elegans and intestinal parasitic nematodes, IVM affects pharyngeal pumping and motor activity at concentrations 0.1 to 10 nM (10)(11)(12). Consistent with these effects, glutamate-gated chloride channels (GluCls), the primary nematocidal targets for IVM, are localized in the motor nervous system of these organisms, particularly in motor neuron commissures, lateral and sublateral nerve cords, amphids, and pharyngeal neurons (13).…”

Study of the nematode putative GABA type‐A receptor subunits: evidence for modulation by ivermectin

“…The antiparasitic effects of ivermectin (IVM) are known to be (i) paralysis of the pharyngeal muscle (Geary et al 1993;Martin 1996), and (ii) paralysis of the somatic muscle (Kass et al 1980;Boisvenue et al 1983;Holden-Dye et al 1988;Holden-Dye and Walker 1990). Attempts to elucidate the mode of action of IVM have therefore been focused on the effects of IVM on the neuromuscular system in nematodes.…”

“…Several lines of evidence have shown that IVM and its analogous avermectins (AVM) interact with GABA receptors (Holden-Dye et al 1988;Martin and Pennington 1989;Holden-Dye and Walker 1990;Ros-Moreno et al 1999), and cause paralysis of the somatic musculature in nematodes (Kass et al 1980;Boisvenue et al 1983). These studies were performed on in situ preparations with unknown subunit composition and the drugs could have acted on multiple receptors.…”