Antiophidic activity of the secondary metabolite lupeol isolated from Zanthoxylum monogynum

• Published in: Toxicon (Oxford) Vol. 193; pp. 38 - 47
• Main Authors: Dos Santos, Benedito Matheus, Ferreira, Glaucio Monteiro, Tavares, Maurício Temotheo, De Bona, Júlio César, Hirata, Mario Hiroyuki, De Paula, Vanderlúcia Fonseca, Saturnino, Klaus Casaro, Soares, Andreimar Martins, Mendes, Mirian Machado
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-04-2021
• Subjects: Animals; Antiophidic; Bothrops; Bothrops alternatus; Crotalid Venoms - toxicity; Mice; Molecular dynamics; Pentacyclic Triterpenes - isolation & purification; Snake venom; South America; Triterpenoid; Zanthoxylum; Zanthoxylum monogynum A.St.-hil; South America; Antiophidic; Molecular dynamics; Snake venom; Zanthoxylum monogynum A.St.-hil; Bothrops alternatus; Triterpenoid
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2021.01.018

Previous studies have demonstrated the potential antiophidic activity of Zanthoxylum monogynum A.St.-Hil. a tree from the Rutaceae family native to South America. In this present contribution, we demonstrate the activity of the metabolite lupeol, a triterpenoid isolated from the stem bark of Z. monogynum against the harmful effects of the Bothrops alternatus venom. We investigated the antiophidic properties of lupeol, for this purpose, and use crude venom (Pb) incubated with lupeol in different concentrations, testing in vitro experiments and inoculated in mice for inhibitory evaluations in vivo. Besides, we tried to elucidate through the molecular dynamics the mechanism of action of lupeol with the bothropic thrombin-like toxin Jararacussin-I; the acidic phospholipase A2 toxin BthA-I from Bothrops jararacussu and the metalloproteinase toxin BmooMP-I from Bothrops moojeni. In our results, we demonstrated the potential inhibitory effect upon coagulant, phospholipasic and myotoxic activities of the bothropic venom, previously incubated with lupeol. We found that lupeol triterpenoid was able to partially inhibit local and systemic damage caused by snake venom toxins. Our in silico results demonstrate that lupeol is capable of interacting and altering the activity of the thrombin-like toxin Jararacussin-I, and capable of interacting with the BthA-I acidic PLA2, both toxins present in Bothrops snakes venom, thus demonstrating the pharmacological potential of this compound for the treatment of bothropic accidents.
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•Antiophidic serotherapy is not able to reduce the envenomation local effects.•When previously incubated with lupeol the venom myotoxic activity is reduced.•Lupeol can partially inhibit the clotting and phospholipase activity induced by the bothropic venom.•In the presence of lupeol the thrombin-like toxin Jararacusina-I undergoes a conformational change.