The actions of varenicline on alkaloids from Conium maculatum (poison hemlock), Lupinus sulphureus (sulphur lupine) and Nicotiana glauca (tree tobacco)

Abstract

Evidence-based therapies to manage the clinical signs of intoxication caused by toxic plants in livestock are lacking. For that reason, the aim of this work was to develop a drug-based intervention for the management of clinical signs of piperidine alkaloid intoxication in livestock. The actions of anabasine, coniine, γ-coniceine, and two total alkaloid extracts from Lupinus sulphureus were compared in the presence and absence of the nicotinic acetylcholine receptor partial agonist varenicline in RD cells, mice and goats. Pretreatment of RD cells with 10.0 μM varenicline significantly shifted the anabasine fifty percent effective concentration (EC₅₀) value to a greater concentration and blocked the response of the cells to coniine. γ-coniceine did not have any effect on RD cells as measured by membrane potential sensing dye. Swiss Webster mice median lethal dose (LD₅₀) values for anabasine, coniine, γ-coniceine were 1.5, 5.5, and 3.7 mg/kg respectively, and pretreatment with 10.0 mg/kg i. p. dosed varenicline shifted the LD₅₀ values to 4.2, 9.1, and 4.3 mg/kg respectively. The rodent LD₅₀ value of the Pendelton, WA L. sulphureus quinolizidine alkaloid extract was shifted to a lesser concentration by varenicline while the Ritzville, WA L. sulphureus piperidine alkaloid extract was shifted to a greater concentration by varenicline. The clinical signs of intoxication in goats orally dosed with Conium maculatum were exacerbated by 0.5, 1.0 and 10.0 mg/kg i. v. dosed varenicline. These results suggest that varenicline was effective at shifting piperidine alkaloid EC₅₀ values in RD cells and increasing piperidine but not quinolizidine alkaloid LD₅₀ values in mice and was not useful at managing the clinical signs of poison hemlock intoxication in goats.