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

Autor(es):Mostrar menos -

Lima, Sunamita de Carvalho ^[1] ; Porta, Lucas de Carvalho ^[1] ; Lima, Alvaro da Costa ^[1] ; Campeiro, Joana D'Arc ^[1] ; Meurer, Ywlliane ^[2] ; Teixeira, Nathalia Bernardes ^[3] ; Duarte, Thiago ^[1] ; Oliveira, Eduardo Brandt ^[4] ; Picolo, Gisele ^[3] ; Godinho, Rosely Oliveira ^[1] ; Silva, Regina Helena ^[1] ; Furuie Hayashi, Mirian Akemi ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo UNIFESP, Dept Farmacol, EPM, Sao Paulo - Brazil

^[2] Univ Fed Rio Grande do Norte UFRN, Dept Fisiol, Natal, RN - Brazil

^[3] Inst Butantan, Lab Especial Dor & Sinalizacao, Sao Paulo - Brazil

^[4] Univ Sao Paulo USP RP, Dept Bioquim & Imunol, Ribeirao Preto - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS Neglected Tropical Diseases; v. 12, n. 8 AUG 2018.
• Citações Web of Science: 2

Resumo

The high medical importance of Crotalus snakes is unquestionable, as this genus is the second in frequency of ophidian accidents in many countries, including Brazil. With a relative less complex composition compared to other genera venoms, as those from the Bothrops genus, the Crotalus genus venom from South America is composed basically by the neurotoxin crotoxin (a phospholipase A2), the thrombin-like gyroxin (a serinoprotease), a very potent aggregating protein convulxin, and a myotoxic polypeptide named crotamine. Interestingly not all Crotalus snakes express crotamine, which was first described in early 50s due to its ability to immobilize animal hind limbs, contributing therefore to the physical immobilization of preys and representing an important advantage for the envenoming efficacy, and consequently, for the feeding and survival of these snakes in nature. Representing about 10-25% of the dry weight of the crude venom of crotamine-positive rattlesnakes, the polypeptide crotamine is also suggested to be of importance for antivenom therapy, although the contribution of this toxin to the main symptoms of envenoming process remains far unknown until now. Herein, we concomitantly performed in vitro and in vivo assays to show for the first time the dose-dependent response of crotamine-triggered hind limbs paralysis syndrome, up to now believed to be observable only at high (sub-lethal) concentrations of crotamine. In addition, ex vivo assay performed with isolated skeletal muscles allowed us to suggest here that compounds active on voltage-sensitive sodium and/or potassium ion channels could both affect the positive inotropic effect elicited by crotamine in isolated diaphragm, besides also affecting the hind limbs paralysis syndrome imposed by crotamine in vivo. By identifying the potential molecular targets of this toxin, our data may contribute to open new roads for translational studies aiming to improve the snakebite envenoming treatment in human. Interestingly, we also demonstrate that the intraplantal or intraperitoneal (ip) injections of crotamine in mice do not promote pain. Therefore, this work may also suggest the profitable utility of non-toxic analogs of crotamine as a potential tool for targeting voltage-gated ion channels in skeletal muscles, aiming its potential use in the therapy of neuromuscular dysfunctions and envenoming therapy. (AU)

• Processo FAPESP: 13/13392-4 - Avaliação do uso dos análogos da crotamina em diagnóstico ou terapia
• Beneficiário: Mirian Akemi Furuie Hayashi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/07019-4 - Papel da via extracelular AMP cíclico-adenosina na fisiopatologia do sistema respiratório e do sistema neuromuscular esquelético
• Beneficiário: Rosely Oliveira Godinho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/02413-1 - Validação da crotamina como biomarcador e avaliação do seu potencial uso na terapia de doenças humanas
• Beneficiário: Mirian Akemi Furuie Hayashi
• Modalidade de apoio: Auxílio à Pesquisa - Regular