Levamisole-resistant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors.

In recent years significant progress has been made in understanding the ecology, epidemiology and related morbidity and development of new tools for the control of soil-transmitted helminths. Such knowledge has recognized the impact of helminth infections on the health of infected groups and has created a rational basis for their control. Schoolchildren harbour some of the most intense helminthic infections, which produce adverse effects on health, growth and scholastic performance. However, although great effort has been put into targeting school-age children, women of child-bearing age and pre-school children are two other groups at high risk of morbidity due to intestinal nematode infections. Highly effective and safety-tested, single-dose anthelminthic drugs are now available, permitting periodical deworming of schoolchildren and other high-risk groups at affordable prices. Four anthelminthics against all intestinal nematodes are included in the WHO Essential Drug List (albendazole, levamisole, mebendazole and pyrantel). Recently ivermectin has also been registered for use against Strongyloides stercoralis in humans. Several well-monitored country experiences have shown that chemotherapy-based control of morbidity due to soil-transmitted helminths is possible and highly cost-effective.

Control strategies for human intestinal nematode infections

Avermectin B1a, a macrocyclic lactone with broad spectrum anthelmintic activity, affects neuromuscular transmission in the lobster stretcher muscle. Perfusion of the muscle with 1-10 microgram of the drug per ml eliminates inhibitory postsynaptic potentials within a few minutes. Intracellularly recorded excitatory postsynaptic potentials are gradually reduced in amplitude over 20-30 min, and their falling phases become faster; there is no effect, however, on extracellularly recorded excitatory potentials. Avermectin B1a reduced the input resistance of the muscle fibers with a time course similar to that of the reduction of excitatory potentials. Washing for up to 2 hr with drug-free solution fails to reverse the drug's effects. However, perfusion with 20 microgram of picrotoxin per ml results in recovery of the excitatory potentials and input resistance. Avermectin B1a also blocks the firing of the crayfish stretch receptor neuron, and this block is also reversed by picrotoxin. We hypothesize that the reduction in excitatory postsynaptic potentials after avermectin B1a treatment is caused solely by reduction in membrane resistance; additional experiments suggest that the reduction in membrane resistance is due to the opening of membrane Cl- channels, perhaps including those regulated by gamma-aminobutyric acid at the inhibitory synapse.

https://www.pnas.org/content/pnas/76/4/2062.full.pdf

Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance

This paper reviews sites of action of anthelmintic drugs including: (1) levamisole and pyrantel, which act as agonists at nicotinic acetylcholine receptors of nematodes; (2) the avermectins, which potentiate or gate the opening of glutamate-gated chloride channels found only in invertebrates; (3) piperazine, which acts as an agonist at GABA gated chloride channels on nematode muscle; (4) praziquantel, which increases the permeability of trematode tegument to calcium and results in contraction of the parasite muscle; (5) the benzimidazoles, like thiabendazole, which bind selectively to parasite β-tubulin and prevents microtubule formation; (6) the proton ionophores, like closantel, which uncouple oxidative phosphorylation; (7) diamphenethide and clorsulon, which selectively inhibit glucose metabolism of Fasciola and; (8) diethylcarbamazine, which appears to interfere with arachidonic acid metabolism of filarial parasites and host. The review concludes with brief comments on the development of anthelmintics in the future.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0031182097001029

Target sites of anthelmintics

Publisher Summary This chapter focuses on receptors for the neurotransmitter molecule GABA (γ-aminobutyric acid) with particular emphasis on insect GABA receptors. It discusses GABA receptors of the insect nervous system and insect muscle. GABAergic neurons are found in the brain, spinal cord, and ganglia of the mammalian nervous system. Ionophoretic application of GABA on to mammalian neurons normally results in an increased membrane conductance and an inhibitory (hyperpolarizing) response of the cell under test. GABA-sensitive cells have been detected in sympathetic ganglia cerebral cortex and Deiter's nucleus. Most responses are attributable to a GABA-operated chloride channel; they are blocked by bicuculline, the active form of which is the 1S,9R-(-)isomer and picrotoxin. The chapter also discusses GABA receptors of invertebrates other than insects, insect GABA receptors as targets for insecticides, and GABA receptors as members of a ligand-operated receptor super-family.

GABA receptors of insects

Die somatische Muskulatur vonAscaris lumbricoides wird durchγ-Aminobuttersaure in Konzentrationen von 10−6-10−5M vollig gehemmt. Eine hnliche Hemmung wird durch Piperazin (10−3M) erzielt. Beide Substanzen steigern die Cl-Permeabilitat der Muskelmembran.

Inhibitory action ofγ-aminobutyric acid (GABA) onAscaris muscle

The effects of piperazine on Ascaris muscle cells have been investigated with electrophysiological techniques. These cells have an average resting potential of about 30 mV interrupted by rhythmic spikes of myogenic origin (1 to 7 spikes/sec). With piperazine (10-3, w/v), the average resting potential increases above 40 mV and the pacemaker activity is suppressed. These changes are similar to those temporarily produced in the same cells by the electrical stimulation of inhibitory nerve fibres. Electrophoretic application of piperazine to different areas of the muscle cells shows that this drug hyperpolarizes their membrane only when applied to the region where both excitatory and inhibitory neuromuscular synapses are located. The degree of muscle hyperpolarization induced by piperazine depends upon the extracellular chloride concentration, decreasing when a fraction of the chloride ions is replaced by the larger, supposedly nonpenetrating, sulphate anions. Piperazine may, therefore, be regarded as a pharmacological analogue of a natural inhibitory transmitter.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1964.tb01701.x

Mechanism of the paralysing action of piperazine on ascaris muscle.

PIPERAZINE is the drug most commonly used for the treatment of ascariasis, in preference to other anthelmintics, because it produces a flaccid paralysis of the parasites1 rather than hyperactivity. Though no direct evidence was available, it was suggested that such paralysis might be due to a curare-like effect, since piperazine prevents the stimulating action of acetylcholine on Ascaris muscle2.

T. Morales

Papers

Inhibitory action ofγ-aminobutyric acid (GABA) onAscaris muscle

Mechanism of the paralysing action of piperazine on ascaris muscle.

Action of piperazine on the neuromuscular system of ascaris lumbricoides.