Pharmacological characterization of crotamine effects on mice hind limb paralysis employing both ex vivo and in vivo assays: Insights into the involvement of voltage-gated ion channels in the crotamine action on skeletal muscles

摘要

Author summary Representing more than 10% of the dry weight of the crude venom of crotamine-positive rattlesnakes, crotamine may act as toxin mainly by imposing the physical immobilization of preys. Its presence was described to be important for antivenom therapy, although the knowledge on the effective contribution of crotamine to the main symptoms of envenoming process remains elusive and limited. Herein, we show for the first time the dose-dependent response for the hind limbs paralysis syndrome promoted by crotamine. We also report herein that compounds active on voltage-sensitive sodium and/or potassium ion channels can affect the positive inotropic effect elicited by crotamine in vitro in isolated diaphragm and also in the hind limbs paralysis syndrome triggered by crotamine in vivo. This potential targeting of voltage-sensitive sodium and/or potassium ion channels suggested here for crotamine may contribute to open new roads for translational studies aiming to improve the snakebite envenoming treatment in human. More importantly, nociceptive threshold evaluation demonstrated that crotamine does not trigger pain, and therefore, we also suggest crotamine as a potential tool for targeting voltage-gated ion channels present in skeletal muscles, with potential to be used as a lead compound to develop drugs for neuromuscular dysfunctions therapy.