Laboratory of Technology and Pharmaceutical Biotechnology (Tecbiofar), College of Pharmacy, Federal University of Rio Grande do Norte, Avenue General Gustavo Cordeiro de Farias, S/N, Petrópolis, Natal 59012-570, Brazil.
Laboratory of Technology and Pharmaceutical Biotechnology (Tecbiofar), College of Pharmacy, Federal University of Rio Grande do Norte, Avenue General Gustavo Cordeiro de Farias, S/N, Petrópolis, Natal 59012-570, Brazil; Chemistry Institute, Federal University of Rio Grande do Norte, Avenue Senador Salgado Filho, 3000, Lagoa Nova, Natal 59072-970, Brazil.
Biomed Pharmacother. 2022 Apr;148:112766. doi: 10.1016/j.biopha.2022.112766. Epub 2022 Mar 2.
Bothrops leucurus is responsible for most cases of snakebite in Northeast Brazil; however, this species is not included in the pool of venoms used in antivenom production in Brazil. The serotherapy has logistical and effectiveness limitations, which stimulates the search for therapeutic alternatives. Chlorogenic acid and rosmarinic acid present several biological activities, but their antiophidic potential has been poorly explored. Thus, the aim of this approach was to evaluate the potential inhibitory effects of these compounds on B. leucurus venom. Initially, the enzymatic inhibition of toxins was evaluated in vitro. Then, anti-hemorrhagic, anti-myotoxic, and anti-edematogenic assays were performed in vivo, as well analysis of several biochemical markers and hemostatic parameters. In addition, the interaction of inhibitors with SVMP and PLA was investigated by docking analysis. Results revealed that compounds inhibited in vitro the enzymatic activities and venom-induced edema, with a decrease in both myeloperoxidase and interleukin quantification. The inhibitors also attenuated the hemorrhagic and myotoxic actions and mitigated changes in serum biochemical and hemostatic markers, as well as decreased lipid peroxidation in liver and kidney tissues. Docking analysis revealed attractive interactions of both inhibitors with the zinc-binding site of SVMP and, in the case of PLA, chlorogenic acid showed a similar inhibition mechanism to that described for rosmarinic acid. The results evidenced the antiophidic potential of both compounds, which showed higher efficiency than antivenom serum. Thus, both inhibitors are promising candidates for future adjuvants to be used to complement antivenom serotherapy.
矛头蝮是巴西东北部造成大多数蛇伤的元凶；然而，这种蛇并没有被纳入巴西抗蛇毒血清生产的毒液库中。血清疗法在物流和有效性方面存在限制，这刺激了对治疗替代方案的探索。绿原酸和迷迭香酸具有多种生物活性，但它们的抗蛇毒潜力尚未得到充分探索。因此，本研究旨在评估这些化合物对矛头蝮蛇毒的潜在抑制作用。首先，在体外评估了毒素的酶抑制作用。然后，在体内进行了抗出血、抗肌毒性和抗水肿作用的检测，以及对几种生化标志物和止血参数的分析。此外，通过对接分析研究了抑制剂与 SVMP 和 PLA 的相互作用。结果表明，这些化合物在体外抑制了毒素的酶活性和蛇毒诱导的水肿，减少了髓过氧化物酶和白细胞介素的定量。抑制剂还减轻了出血和肌毒性作用，并减轻了血清生化和止血标志物的变化，同时降低了肝和肾组织中的脂质过氧化。对接分析显示，两种抑制剂与 SVMP 的锌结合位点都具有吸引力的相互作用，而对于 PLA，绿原酸表现出与迷迭香酸类似的抑制机制。这些结果证明了这两种化合物的抗蛇毒潜力，其效率高于抗蛇毒血清。因此，这两种抑制剂都是未来用于补充抗蛇毒血清治疗的潜在佐剂的候选物。
