The bioflavonoids rutin and rutin succinate neutralize the toxins of B. jararaca venom and inhibit its lethality

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dc.contributorLab. Fisiopatologiapt_BR
dc.contributor(LDI) Lab. Desenvolvimento e Inovação Industrialpt_BR
dc.contributor.authorSachetto, Ana Teresa Azevedopt_BR
dc.contributor.authorMiyamoto, Jackson Gabrielpt_BR
dc.contributor.authorTashima, Alexandre Keijipt_BR
dc.contributor.authorSouza, Ana Olívia dept_BR
dc.contributor.authorSantoro, Marcelo Laramipt_BR
dc.date.accessioned2022-03-17T19:10:20Z-
dc.date.available2022-03-17T19:10:20Z-
dc.date.issued2022pt_BR
dc.identifier.citationSachetto ATA, Miyamoto JG, Tashima AK, Souza AO, Santoro ML. The bioflavonoids rutin and rutin succinate neutralize the toxins of B. jararaca venom and inhibit its lethality. Front. Pharmacol.. 2022 Feb; in press. doi:10.3389/fphar.2022.828269.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/4262-
dc.description.abstractThe venom of the Brazilian pit viper Bothrops jararaca (BjV) is a complex mixture of molecules, and snake venom metalloproteinases (SVMP) and serine proteinases (SVSP) are the most abundant protein families found therein. Toxins present in BjV trigger most of the deleterious disturbances in hemostasis observed in snakebites, i.e., thrombocytopenia, hypofibrinogenemia and bleedings. The treatment of patients bitten by snakes still poses challenges and the bioflavonoid rutin has already been shown to improve hemostasis in an experimental model of snakebite envenomation. However, rutin is poorly soluble in water; in this study, it was succinylated to generate its water-soluble form, rutin succinate (RS), which was analyzed comparatively regarding the chemical structure and characteristic features of rutin. Biological activities of rutin and RS were compared on hemostatic parameters, and against toxic activities of crude BjV in vitro. In vivo, C57BL/6 mice were injected i.p. with either BjV alone or pre-incubated with rutin, RS or 1,10-phenanthroline (o-phe, an SVMP inhibitor), and the survival rates and hemostatic parameters were analyzed 48 h after envenomation. RS showed the characteristic activities described for rutin – i.e., antioxidant and inhibitor of protein disulfide isomerase – but also prolonged the clotting time of fibrinogen and plasma in vitro. Differently from rutin, RS inhibited typical proteolytic activities of SVMP, as well as the coagulant activity of BjV. Importantly, both rutin and RS completely abrogated the lethal activity of BjV, in the same degree as o-phe. BjV induced hemorrhages, falls in RBC counts, thrombocytopenia and hypofibrinogenemia in mice. Rutin and RS also improved the recovery of platelet counts and fibrinogen levels, and the development of hemorrhages was totally blocked in mice injected with BjV incubated with RS. In conclusion, RS has anticoagulant properties and is a novel SVMP inhibitor. Rutin and RS showed different mechanisms of action on hemostasis. Only RS inhibited directly BjV biological activities, even though both flavonoids neutralized B. jararaca toxicity in vivo. Our results showed clearly that rutin and RS show a great potential to be used as therapeutic compounds for snakebite envenomation.pt_BR
dc.description.sponsorship(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.description.sponsorship(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.format.extent828269pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofFrontiers in Pharmacologypt_BR
dc.rightsOpen accesspt_BR
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/pt_BR
dc.titleThe bioflavonoids rutin and rutin succinate neutralize the toxins of B. jararaca venom and inhibit its lethalitypt_BR
dc.typeArticlept_BR
dc.rights.licenseCC BYpt_BR
dc.identifier.doi10.3389/fphar.2022.828269pt_BR
dc.identifier.urlhttps://doi.org/10.3389/fphar.2022.828269pt_BR
dc.contributor.external(USP) Universidade de São Paulopt_BR
dc.contributor.external(UNIFESP) Universidade Federal de São Paulopt_BR
dc.identifier.citationvolume13pt_BR
dc.subject.keywordcoagulationpt_BR
dc.subject.keywordhemostasispt_BR
dc.subject.keywordrutinpt_BR
dc.subject.keywordsnake venompt_BR
dc.subject.keywordantivenompt_BR
dc.relation.ispartofabbreviatedFront Pharmacolpt_BR
dc.identifier.citationabntv. 13, 828269, fev. 2022pt_BR
dc.identifier.citationvancouver2022 Feb; 13:828269pt_BR
dc.contributor.butantanSouza, Ana Olívia de|:Pesquisador|:Lab. Fisiopatologiapt_BR
dc.contributor.butantanSantoro, Marcelo Larami|:Pesquisador|:Lab. Desenvolvimento e Inovação Industrialpt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.sponsorship.butantan2008/06524-3pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.sponsorship.butantan2013/25177-0pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.sponsorship.butantan2018/26015-8pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.sponsorship.butantan2019/07618-6pt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.sponsorship.butantan312469/2018-7pt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.sponsorship.butantan309980/2021-6pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.sponsorship.butantan2017/20106-9pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
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item.languageiso639-1English-
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