Effects of the anthelmintic drug PF1022A on mammalian tissue and cells

Abstract

Nematode infections cause human morbidity and enormous economic loss in livestock. Since resistance against currently available anthelmintics is a worldwide problem, there is a continuous need for new compounds. The cyclooctadepsipeptide PF1022A is a novel anthelmintic that binds to the latrophilin-like transmembrane receptor important for pharyngeal pumping in nematodes. Furthermore, PF1022A binds to GABA receptors, which might contribute to the anthelmintic effect. Like other cyclodepsipeptides, PF1022A acts as an ionophore. However, no correlation between ionophoric activity and anthelmintic properties was found. This is the first study describing the effect of PF1022A on mammalian cells and tissues. While channel-forming activity was observed already at very low concentrations, changes in intracellular ion concentrations and reduction of contractility in isolated guinea-pig ileum occurred at multiples of anthelmintically active concentrations.PF1022A did not induce necrotic cell death indicated by complete lack of cellular lactate dehydrogenase release. In contrast, apoptosis induction via the mitochondrial pathway was suggested for long-term drug treatment at high concentrations due to numerous apoptotic morphological changes as well as mitochondrial membrane depolarisation. Short time effects were based on cell cycle blockade in G 0 /G 1 phase. Additionally, the cell cycle and apoptosis regulating proteins p53, p21 and bax, but not Bcl-2 were shown to impact on PF1022A-induced cytotoxicity. However, since PF1022A-induced cytotoxicity was found at drug concentrations higher than those used in anthelmintic treatment, it can be suggested that PF1022A intake might not impair human or animal health. Thus, PF1022A seems to be a safe alternative to other anthelmintic drugs.

The Cyclooctadepsipeptide Anthelmintic Emodepside Differentially Modulates Nematode, Insect and Human Calcium-Activated Potassium (SLO) Channel Alpha Subunits

“…Our observations, and previous reports, indicate that the modulation of the Ca 2+ -activated K + channels in HEK293 cells by emodepside cannot be ascribed to an elevation of intracellular Ca 2+ . The parent compound for emodepside, the cyclooctadepsipeptide PF1022A, does not increase intracellular Ca 2+ in CaCo-2 cells [ 34 ]. Here we conducted a similar study on HEK293 cells and showed that a supramaximal concentration of emodepside (100μM) had no significant effect on the intracellular concentration of Ca 2+ .…”

Worms take to the slo lane: a perspective on the mode of action of emodepside

“…A similar train of thought suggests that at micromolar concentrations of emodepside, a concentration that is difficult to keep in aqueous solution, emodepside would appear in the membrane at a 1:1 emodepside/lipid ratio where one might expect to see additional membrane perturbant effects. Indeed, this expectation is realised by the report that the parent compound of emodepside, PF1022A, has ionophore properties and directly confers ion channel activity on membranes, although this appears unrelated to its anthelmintic action (Geßner et al 1996; Dornetshuber et al 2009).

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Brain penetration of emodepside is increased in P‐glycoprotein‐deficient mice and leads to neurotoxicosis

“…Quantification of the neurotoxic potential of EMO in PGP mut and PGP WT mice on the rotarod Next, we aimed to elucidate whether the increased brain penetration of EMO in the PGP mut mice may provoke neurological toxicity. As data about an interaction of EMO with vertebrate receptors are limited (Dornetshuber et al, 2009;Crisford et al, 2011), it was not clear which kind of effects could be expected in the case of EMO-induced neurological toxicity in mice. Repeated oral dose toxicity studies in rats and mice revealed effects on the neurological function, behavior, ataxia, and increased motility.…”

“…It is well established that EMO exhibits high antiparasitic efficacy even in multiresistant parasite strains and low toxicity in mammals (Conder et al, 1995;von Samson-Himmelstjerna et al, 2000;Harder et al, 2003Harder et al, , 2005Jeschke et al, 2005;Dornetshuber et al, 2009). During approval of this new drug entity, EMO was identified as a substrate of P-glycoprotein (Pgp) which is coded by the multidrug resistance gene (MDR1) (syn.…”