|Green, Benedict - Ben|
|KEM, WILLIAM - University Of Florida|
Submitted to: Toxicon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/11/2018
Publication Date: 3/15/2018
Citation: Green, B.T., Lee, S.T., Keele, J.W., Welch, K.D., Cook, D., Pfister, J.A., Kem, W.R. 2018. Complete inhibition of fetal movement in the day 40 pregnant goat model by the piperidine alkaloid anabasine but not related alkaloids. Toxicon. 144:61-67. https://doi.org/10.1016/j.toxicon.2018.02.007.
Interpretive Summary: The goal of this research was to determine if cell-culture studies are an accurate predictor of the ability of toxins to cause birth defects in livestock. Results from our experiments suggest that cell culture can provide valuable information about plant toxins but animal models are still required to validate the potential of a toxins to cause developmental defects.
Technical Abstract: Four chemically similar alkaloids, anabasine, anabaseine, epibatidine and dimethylphenylpiperazinium (DMPP), are potent nicotinic acetylcholine receptor agonists of fetal muscle nicotinic acetylcholine receptors in human TE-671 cells. Based on results with these cells, we hypothesized that these alkaloids would completely inhibit ultrasound-monitored fetal movement in a goat model. Pregnant goats were dosed with each compound I.V. with anabasine, anabaseine, epibatidine, DMPP, or saline control on day 40 of gestation and the number of fetal movements per five minutes sample was periodically measured by ultrasound for 8 hours. The differences among does in fetal movements were more consistent at dosing and following recovery for doses of anabasine above 0.125 mg/kg compared to the other compounds and dosages. Anabasine actions were dose-dependent with an IC50 value of ~0.1 mg/kg, and, at a dose of 0.8 mg/kg, completely inhibited fetal movement for 1.5 hours after dosing. Anabaseine, epibatidine, and DMPP failed to completely inhibit fetal movement in day 40 pregnant goats at doses predicted to be effective. These results suggest that while experiments with TE-671 cells provide valuable information and predictions of the actions of plant alkaloids on fetal movement, in vivo experiments are still required in order to determine the ability of an alkaloid to inhibit fetal movement in livestock species. Moreover, other pharmacological properties such as receptor differences between mammalian species and differences in the pharmacokinetic properties of the alkaloids also are likely to weaken teratologic predictions based solely on the in vitro data.