Naz Shagufta, Al Kury Lina Tariq, Nadeem Humaira, Shah Fawad Ali, Ullah Aman, Paracha Rehan Zafar, Imran Muhammad, Li Shupeng
Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan.
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People's Republic of China.
J Inflamm Res. 2022 Jun 25;15:3643-3660. doi: 10.2147/JIR.S357082. eCollection 2022.
Several studies revealed that alcohol utilization impairs memory in adults; however, the underlying mechanism is still unclear. The production of inflammatory markers and reactive oxygen species (ROS) plays a major role in neurodegeneration, which leads to memory impairment. Therefore, targeting neuroinflammation and oxidative distress could be a useful strategy for abrogating the hallmarks of ethanol-induced neurodegeneration. Moreover, several studies have demonstrated multiple biological activities of thiazolidine derivatives including neuroprotection.
In the current study, we synthesized ten (10) new thiazolidine-4-carboxylic acid derivatives (P1-P10), characterized their synthetic properties using proton nuclear magnetic resonance (H-NMR) and carbon-13 NMR, and further investigated the neuroprotective potential of these compounds in an ethanol-induced neuroinflammation model.
Our results suggested altered levels of antioxidant enzymes associated with an elevated level of tumor necrosis factor-alpha (TNF-α), nuclear factor-κB (p-NF-κB), pyrin domain-containing protein 3 (NLRP3), and cyclooxygenase-2 (COX-2) in ethanol-treated animals. Ethanol treatment also led to memory impairment in rats, as assessed by behavioral tests. To further support our notion, we performed molecular docking studies, and all synthetic compounds exhibited a good binding affinity with a fair bond formation with selected targets (NF-κB, TLR4, NLRP3, and COX-2).
Overall, our results revealed that these derivatives may be beneficial in reducing neuroinflammation by acting on different stages of inflammation. Moreover, P8 and P9 treatment attenuated the neuroinflammation, oxidative stress, and memory impairment caused by ethanol.
多项研究表明，酒精的摄入会损害成年人的记忆力；然而，其潜在机制仍不清楚。炎症标志物和活性氧（ROS）的产生在神经退行性变中起主要作用，而神经退行性变会导致记忆障碍。因此，针对神经炎症和氧化应激可能是消除乙醇诱导的神经退行性变特征的有效策略。此外，多项研究已证明噻唑烷衍生物具有多种生物活性，包括神经保护作用。
在本研究中，我们合成了十种新的噻唑烷-4-羧酸衍生物（P1-P10），利用质子核磁共振（H-NMR）和碳-13核磁共振对其合成性质进行了表征，并在乙醇诱导的神经炎症模型中进一步研究了这些化合物的神经保护潜力。
我们的结果表明，在乙醇处理的动物中，抗氧化酶水平发生改变，同时肿瘤坏死因子-α（TNF-α）、核因子-κB（p-NF-κB）、含pyrin结构域蛋白3（NLRP3）和环氧化酶-2（COX-2）水平升高。通过行为测试评估，乙醇处理还导致大鼠记忆障碍。为进一步支持我们的观点，我们进行了分子对接研究，所有合成化合物与选定靶点（NF-κB、TLR4、NLRP3和COX-2）均表现出良好的结合亲和力和合理的键形成。
总体而言，我们的结果表明，这些衍生物可能通过作用于炎症的不同阶段来减轻神经炎症。此外，P8和P9处理减轻了乙醇引起的神经炎症、氧化应激和记忆障碍。
