Ullah Aman, Al Kury Lina Tariq, Althobaiti Yusuf S, Ali Tahir, Shah Fawad ALi
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates.
J Inflamm Res. 2022 Jul 11;15:3873-3890. doi: 10.2147/JIR.S351913. eCollection 2022.
The study investigated the effect of newly synthesized benzimidazole derivatives against ethanol-induced neurodegeneration. According to evidence, ethanol consumption may cause a severe insult to the central nervous system (CNS), resulting in mental retardation, neuronal degeneration, and oxidative stress. Targeting neuroinflammation and oxidative stress may be a useful strategy for preventing ethanol-induced neurodegeneration.
Firstly, the newly synthesized compounds were subjected to molecular simulation and docking in order to predict ligand binding status. Later, for in vivo observations, adult male Sprague Dawley rats were used for studying behavioral and oxidative stress markers. ELIZA kits were used to analyse tumour necrosis factor-alpha (TNF-), nuclear factor-B (NF-B), interleukin (IL-18), and pyrin domain-containing protein 3 (NLRP3) expression, while Western blotting was used to measure IL-1 and Caspase-1 expression.
Our findings suggested that altered levels of antioxidant enzymes were associated with elevated levels of TNF-α, NF-B, IL-1, IL-18, Caspase-1, and NLRP3 in the ethanol-treated group. Furthermore, ethanol also caused memory impairment in rats, as measured by behavioural tests. Pretreatment using selected benzimidazole significantly increased the combat of the brain against ethanol-induced oxidative stress. The neuroprotective effects of benzimidazole derivatives were promoted by their free radical scavenging activity, augmentation of endogenous antioxidant proteins (GST, GSH), and amelioration of lipid peroxide (LPO) and other pro-inflammatory mediators. Molecular docking and molecular simulation studies further supported our hypothesis that the synthetic compounds Ca and Cb had an excellent binding affinity with proper bond formation with their targets (TNF-α and NLRP3).
It is revealed that these benzimidazole derivatives can reduce ethanol-induced neuronal toxicity by regulating the expression of cytokines, antioxidant enzymes, and the inflammatory cascade.
本研究调查了新合成的苯并咪唑衍生物对乙醇诱导的神经退行性变的影响。有证据表明，饮酒可能会对中枢神经系统（CNS）造成严重损害，导致智力迟钝、神经元变性和氧化应激。针对神经炎症和氧化应激可能是预防乙醇诱导的神经退行性变的有效策略。
首先，对新合成的化合物进行分子模拟和对接，以预测配体结合状态。随后，为了进行体内观察，使用成年雄性Sprague Dawley大鼠来研究行为和氧化应激标志物。使用酶联免疫吸附测定（ELISA）试剂盒分析肿瘤坏死因子-α（TNF-α）、核因子-κB（NF-κB）、白细胞介素（IL-18）和含吡喃结构域蛋白3（NLRP3）的表达，同时使用蛋白质印迹法测量IL-1和半胱天冬酶-1（Caspase-1）的表达。
我们的研究结果表明，乙醇处理组中抗氧化酶水平的改变与TNF-α、NF-κB、IL-1、IL-18、Caspase-1和NLRP3水平的升高有关。此外，通过行为测试测量发现，乙醇还会导致大鼠记忆障碍。使用选定的苯并咪唑进行预处理可显著增强大脑对乙醇诱导的氧化应激的抵抗力。苯并咪唑衍生物的神经保护作用通过其自由基清除活性、内源性抗氧化蛋白（谷胱甘肽S-转移酶、谷胱甘肽）的增加以及脂质过氧化物（LPO）和其他促炎介质的改善而得到促进。分子对接和分子模拟研究进一步支持了我们的假设，即合成化合物Ca和Cb与它们的靶点（TNF-α和NLRP3）具有良好的结合亲和力并形成了适当的键。
结果表明，这些苯并咪唑衍生物可通过调节细胞因子、抗氧化酶和炎症级联反应的表达来降低乙醇诱导的神经元毒性。
