Research Article In Vivo Protection against Strychnine Toxicity in Mice by the Glycine Receptor Agonist Ivermectin

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1mg/kg and 5mg/kg ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2mg/kg). Ivermectin, through both routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of up to 80%of animals and a significant delay of strychnine effects in up to 100%of tested animals. Strychnine action developedwithin minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin. 1