Pharmacological Characterization of a Novel Anthelmintic, U-I03426, Using Ascaris suum Neuromuscular Strips
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PF 1 022A (U-103426) is a fermentation-derived novel depsipeptide found to have potent anthelmintic effects against the parasitic nematodes Angiostrongylus cantonensis (Terada, 1992) and Haemonchus contortus (Conder et aI., 1995). Initial studies suggested that this compound works by stimulating the gabergic system and inhibiting the cholinergic system in nematodes (Terada, 1992). Subsequent research has focused on the binding of PFI022A to GABA receptors in an attempt to support that initial hypothesis. In order to further our knowledge of this compound, we examined its effects on the commonly studied gastrointestinal parasite, Ascaris suun, and quantitated its interactions with several known neurotransmitters and neuropeptides. The results of this study showed that intact A. suum and neuromuscular strips isolated from this nematode are highly responsive to PFI022A. The compound relaxed A. suum neuromuscular strips at concentrations >= 1 µM in a time-dependent fashion. Studies using denervated preparations localized the site of action to the nerve cord, unlike most endogenous neuropeptides which act directly on muscle receptors. PF1022A effects were partially mediated by CI- channels, the only GABA-like similarity found in this study. The compound abolished eserine (an acetylcholinesterase inhibitor) contractions, suggesting that it may prevent release of ACh at the pre-synaptic level. Interestingly, PFI022A relaxed preparations stimulated with the excitatory neuropeptide, AF2, possibly through antagonism. These results indicate that PF1022A has a mechanism of action that is unlike the characterized neuropeptides. Further study on this compound will be necessary to determine its exact mechanism of action.