Submitted to: Food and Chemical Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 1, 2013
Publication Date: August 1, 2013
Citation: Green, B.T., Lee, S.T., Welch, K.D., Pfister, J.A., Panter, K.E. 2013. Piperidine, pyridine alkaloid inhibition of fetal movement in a day 40 pregnant goat model. Food and Chemical Toxicology. 58:8-13. Interpretive Summary: In this work, we tested the hypothesis that piperidine alkaloids anabasine and lobeline would be more effective than the pyridine alkaloid myosmine at inhibiting fetal movement in a day 40 pregnant goat model. Unexpectedly, the pyridine alkaloid myosmine was more effective at inhibiting fetal movement than lobeline. We also examined the actions of the three alkaloids in TE-671 cells. Cone snail toxins blocked the actions of two of the alkaloids. One of the alkaloids, lobeline was insensitive to cone snail toxins. These results suggest that lobeline is a "unique ligand" with complex pharmacology, which warrants further investigation. These results suggest that the alkaloids tested in this report are agonists at fetal muscle-type nicotinic receptors and that they have the potential to reduce or inhibit fetal movement in goats.
Technical Abstract: The inhibition of fetal movement is one mechanism behind the development of multiple congenital contracture-type defects and cleft palate in developing fetuses of humans and animals. In this study, we tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also tested the alkaloids for the ability to decrease ultrasound monitored fetal movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, the actions of the alkaloids were concentration-dependent. Anabasine and myosmine were sensitive to alpha conotoxin GI. Lobeline was insensitive to both alpha conotoxins. In the day 40 pregnant goat model, 0.8 mg/kg anabasine abolished fetal movement at 30 and 60 minutes after dosing and fetal movement in pregnant goats dosed with 4 mg/kg lobeline and 5 mg/kg myosmine significantly reduced fetal movement. This study suggests that all three alkaloids tested are fetal muscle-type nAChR agonists and that they significantly decrease fetal movement.