da Silva Pablo Rayff, Apolinário Nadjaele de Melo, Silva Simone Ângela Soares da, Araruna Maria Elaine Cristina, Costa Thássia Borges, E Silva Yvnni M S de Medeiros, da Silva Teresinha Gonçalves, de Moura Ricardo Olímpio, Dos Santos Vanda Lucia
Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual da Paraíba, Campina Grande 58429-500, PB, Brazil.
Laboratório de Ensaios Farmacológicos, Departamento de Farmácia, Universidade Estadual da Paraíba, Campina Grande 58429-500, PB, Brazil.
Pharmaceuticals (Basel). 2023 Oct 5;16(10):1415. doi: 10.3390/ph16101415.
The -acylhydrazone function has been reported as a pharmacophore group of molecules with diverse pharmacological activities, including anti-inflammatory effects. Therefore, this study was designed to evaluate the anti-inflammatory potential of the compound '-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide (JR19) in vivo. The study started with the carrageenan-induced peritonitis model, followed by an investigation of leukocyte migration using the subcutaneous air pouch test and an assessment of the antinociceptive profile using formalin-induced pain. A preliminary molecular docking study focusing on the crystallographic structures of NFκB, iNOS, and sGC was performed to determine the likely mechanism of action. The computational study revealed satisfactory interaction energies with the selected targets, and the same peritonitis model was used to validate the involvement of the nitric oxide pathway and cytokine expression in the peritoneal exudate of mice pretreated with L-NAME or methylene blue. In the peritonitis assay, JR19 (10 and 20 mg/kg) reduced leukocyte migration by 59% and 52%, respectively, compared to the vehicle group, with the 10 mg/kg dose used in subsequent assays. In the subcutaneous air pouch assay, the reduction in cell migration was 66%, and the response to intraplantar formalin was reduced by 39%, particularly during the inflammatory phase, suggesting that the compound lacks central analgesic activity. In addition, a reversal of the anti-inflammatory effect was observed in mice pretreated with L-NAME or methylene blue, indicating the involvement of iNOS and sGC in the anti-inflammatory response of JR19. The compound effectively and significantly decreased the levels of IL-6, TNF-α, IL-17, and IFN-γ, and this effect was reversed in animals pretreated with L-NAME, supporting a NO-dependent anti-inflammatory effect. In contrast, pretreatment with methylene blue only reversed the reduction in TNF-α levels. Therefore, these results demonstrate the pharmacological potential of the novel -acylhydrazone derivative, which acts through the nitric oxide pathway and cytokine signaling, making it a strong candidate as an anti-inflammatory and immunomodulatory agent.
酰腙官能团已被报道为具有多种药理活性（包括抗炎作用）的分子的药效基团。因此，本研究旨在评估化合物“-(3-(1H-吲哚-3-基)亚苄基)-2-氰基乙酰肼（JR19）”在体内的抗炎潜力。该研究始于角叉菜胶诱导的腹膜炎模型，随后通过皮下气囊试验研究白细胞迁移，并使用福尔马林诱导的疼痛评估镇痛情况。进行了一项针对NFκB、诱导型一氧化氮合酶（iNOS）和可溶性鸟苷酸环化酶（sGC）晶体结构的初步分子对接研究，以确定可能的作用机制。计算研究显示与选定靶点具有令人满意的相互作用能，并使用相同的腹膜炎模型来验证一氧化氮途径和细胞因子表达在经L-硝基精氨酸甲酯（L-NAME）或亚甲蓝预处理的小鼠腹膜渗出液中的参与情况。在腹膜炎试验中，与赋形剂组相比，JR19（10和20mg/kg）分别使白细胞迁移减少了59%和52%，后续试验使用10mg/kg剂量。在皮下气囊试验中，细胞迁移减少了66%，对足底注射福尔马林的反应减少了39%，特别是在炎症期，这表明该化合物缺乏中枢镇痛活性。此外，在用L-NAME或亚甲蓝预处理的小鼠中观察到抗炎作用的逆转，表明iNOS和sGC参与了JR19的抗炎反应。该化合物有效且显著降低了白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、白细胞介素-17和干扰素-γ（IFN-γ）的水平，并且在用L-NAME预处理的动物中这种作用被逆转，支持了一氧化氮依赖性抗炎作用。相比之下，用亚甲蓝预处理仅逆转了TNF-α水平的降低。因此，这些结果证明了新型酰腙衍生物的药理潜力，其通过一氧化氮途径和细胞因子信号传导发挥作用，使其成为一种强大的抗炎和免疫调节药物候选物。
