Postgraduate Program in Biochemistry and Bioprospecting, Research Laboratory in Biochemical Pharmacology (LaFarBio), Research Group in Neurobiotechnology (GPN), Center of Chemical, Pharmaceutical and Food Sciences, Federal University of Pelotas (UFPel), CEP 96010- 900, Pelotas, RS, Brazil.
Laboratory of Organic Catalysis and Biocatalysis, Federal University of Grande Dourados (UFGD), 79825-070, Dourados, MS, Brazil.
Chem Biol Interact. 2022 Jan 5;351:109736. doi: 10.1016/j.cbi.2021.109736. Epub 2021 Nov 3.
The aim of the present study was investigate the binding affinity of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) with acetylcholinesterase (AChE). We also evaluated the effect of MTDZ against scopolamine (SCO)-induced amnesia in mice and we looked at the toxicological potential of this compound in mice. The binding affinity of MTDZ with AChE was investigated by molecular docking analyses. For an experimental model, male Swiss mice were treated daily with MTDZ (10 mg/kg, intragastrically (i.g.)) or canola oil (10 ml/kg, i.g.), and induced, 30 min later, with injection of SCO (0.4 mg/kg, intraperitoneally (i.p.)) or saline (0.9%, 5 ml/kg, i.p.) daily. From day 1 to day 10, mice were submitted to the behavioral tasks (Barnes maze, open-field, object recognition and location, Y-maze and step-down inhibitory avoidance tasks), 30 min after induction with SCO. On the tenth day, the animals were euthanized and blood was collected for the analysis of biochemical markers (creatinine, aspartate (AST), and alanine (ALT) aminotransferase). MTDZ interacts with residues of the AChE active site. SCO caused amnesia in mice by changing behavioral tasks. MTDZ treatment attenuated the behavioral changes caused by SCO. In ex vivo assay, MTDZ also protected against the alteration of AChE activity, reactive species (RS) levels, thiobarbituric acid reative species (TBARS) levels, catalase (CAT) activity in tissues, as well as in transaminase activities of plasma caused by SCO in mice. In conclusion, MTDZ presented anti-amnesic action through modulation of the cholinergic system and provided protection from kidney and liver damage caused by SCO.
本研究旨在探讨 5-((4-甲氧基苯基)硫代)苯并[c][1,2,5]噻二唑 (MTDZ) 与乙酰胆碱酯酶 (AChE) 的结合亲和力。我们还评估了 MTDZ 对东莨菪碱 (SCO) 诱导的小鼠健忘症的影响，并观察了该化合物在小鼠中的毒理学潜力。通过分子对接分析研究了 MTDZ 与 AChE 的结合亲和力。在实验模型中，雄性瑞士小鼠每天用 MTDZ（10mg/kg，灌胃）或菜籽油（10ml/kg，灌胃）处理，并在 30 分钟后用 SCO（0.4mg/kg，腹腔注射）或生理盐水（0.9%，5ml/kg，腹腔注射）诱导，每天一次。从第 1 天到第 10 天，在 SCO 诱导后 30 分钟，小鼠进行行为任务（巴恩斯迷宫、旷场、物体识别和定位、Y 迷宫和下踏板抑制性回避任务）。第 10 天，处死动物并采集血液用于生化标志物（肌酐、天门冬氨酸 (AST) 和丙氨酸 (ALT) 氨基转移酶）分析。MTDZ 与 AChE 活性位点的残基相互作用。SCO 通过改变行为任务导致小鼠健忘。MTDZ 处理减轻了 SCO 引起的行为变化。在离体试验中，MTDZ 还防止了 SCO 引起的小鼠组织中 AChE 活性、活性物质 (RS) 水平、硫代巴比妥酸反应物质 (TBARS) 水平、过氧化氢酶 (CAT) 活性以及血浆中转氨酶活性的改变。总之，MTDZ 通过调节胆碱能系统表现出抗健忘作用，并为 SCO 引起的肾和肝损伤提供了保护。
