Selective effects of paraherquamide on Ascaris suum nAChR subtypes
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Abstract
Nematode parasites infest humans and animals causing morbidity and significant economic loss. Ascaris suum lives in the small intestine of the pig. Ascaris infestation of pigs can cause Ascariasis and poor growth rate. Another species, Ascaris lumbricoides infects humans. More than one billion people in the world suffer the Ascaris infestation (Crompton, 1984). Nicotinic anthelmintic compounds, which act on nematode nicotinic acetylcholine receptors (nAChRs), used to treat nematode infestation. However, the long-term repeated intake of one anthelmintic compound may cause the drug resistance. Robertson (1999) suggested that the resistance to anthelmintic compound levamisole may due to the loss of a levamisole-sensitive nAChR subtypes. Paraherquamide is a novel anthelmintic compound and is effective against strains of parasites that are resistant to the known broad-spectrum anthelmintic drugs (Shoop et al., 1990, 1991, 1992). The published data suggests that it behaves like a competitive antagonist of nematode nAChRs located on the nematodesomatic musculature. In this research the effect of paraherquamide on the nematode Ascaris suum nAChRs was investigated at the single-channel level. Membrane vesicles were prepared from collagenase-treated Ascaris muscle flaps. The single-channel currents induced by 30 [mu]M levamisole were recorded using inside-out patches isolated from the vesicles. The channels had conductances ranging from 18 pS to 52 pS. Paraherquamide was added to the bath chamber during recordings to give a final concentration of 0.3-10 [mu]M and its effects on the single-channel currents were monitored. Paraherquamide reduced the probability of channel being open (P[subscript open]) in a concentration-dependent manner. 1 [mu]M paraherquamide selectively reduced the P[subscript open] values of the 45 pS channel; it had less effect on the P[subscript open] of the 35 pS channel, and the smallest effect on the 21 pS channel. This selectivity illustrates that the 21, 35 and 45 pS channels are pharmacologically distinct and suggests structural differences. The present study demonstrates that paraherquamide is an antagonist of the nAChRs located on the somatic musculature of parasitic nematodes and confirms at the single-channel level the selective effect of paraherquamide on the Ascaris nAChRs subtypes.