Laboratory of Pathophysiology, Institute Butantan, São Paulo, São Paulo, Brazil.
Department of Medical Sciences, School of Medicine, University of São Paulo, São Paulo, São Paulo, Brazil.
PLoS Negl Trop Dis. 2018 Oct 11;12(10):e0006774. doi: 10.1371/journal.pntd.0006774. eCollection 2018 Oct.
Snakebites are a major Collective Health problem worldwide. In Brazil, Bothrops jararaca snake venom (BjV) evokes hemostatic disturbances, bleeding manifestations, and redox status imbalance. Specific antivenom therapy, although efficacious to revert most snakebite-induced manifestations, is incapable of treating secondary manifestations, such as oxidative/nitrosative stress. Searching for new complementary therapies that could attenuate physiological derangements triggered by envenomation, we elected to test quercetin-3-rutinoside (rutin) by its potential as both a potent antioxidant and a hemostasis modulatory compound. The activity of rutin was evaluated both on the biological activities of crude BjV in vitro, and in vivo by the ability of rutin (14.4 mg/kg b.w.) to modulate hematological, hemostatic and redox status markers altered by BjV injection (1.6 mg/kg b.w., s.c.) in mice. In vitro, rutin failed to inhibit BjV-induced platelet aggregation and biological activities of major BjV enzymes (metalloproteinases, phospholipases A2, serine proteases, and L-amino acid oxidases). On the other hand, rutin attenuated local hemorrhage, and the increase in reactive species, prevented the fall in RBC counts and fibrinogen levels, diminished tail bleeding and shortened prothrombin time (PT) evoked by envenomation. Furthermore, rutin reduced tissue factor (TF) activity and altered the protein expression of TF in liver, lungs, heart and skin. In conclusion, the disturbances in redox status and hemostatic system induced by B. jararaca envenomation were modulated by rutin, suggesting it has a great potential to be used as an ancillary therapeutic agent for snakebites.
蛇伤是全球范围内的一个主要公共卫生问题。在巴西，矛头蝮蛇毒液（BjV）会引起止血紊乱、出血表现和氧化还原状态失衡。尽管特异性抗蛇毒血清治疗对于逆转大多数蛇咬伤引起的表现是有效的，但它不能治疗继发性表现，如氧化/硝化应激。为了寻找新的补充疗法来减轻蛇毒引起的生理紊乱，我们选择测试槲皮素-3-芸香糖苷（芦丁），因为它具有强大的抗氧化和止血调节化合物的潜力。芦丁的活性通过其在体外对粗制 BjV 的生物学活性的影响，以及在体内通过芦丁（14.4mg/kg bw）调节因 BjV 注射（1.6mg/kg bw，sc）而改变的血液学、止血和氧化还原状态标志物的能力来评估。在体外，芦丁未能抑制 BjV 诱导的血小板聚集和 BjV 主要酶（金属蛋白酶、磷脂酶 A2、丝氨酸蛋白酶和 L-氨基酸氧化酶）的生物学活性。另一方面，芦丁减轻了局部出血，减少了活性物质的增加，防止了红细胞计数和纤维蛋白原水平的下降，减少了尾部出血和凝血酶原时间（PT）的缩短，这是由蛇毒引起的。此外，芦丁降低了组织因子（TF）的活性，并改变了肝脏、肺、心脏和皮肤中 TF 的蛋白表达。总之，B. jararaca 蛇毒引起的氧化还原状态和止血系统紊乱被芦丁调节，这表明它具有作为蛇咬伤辅助治疗剂的巨大潜力。
