Hassan Amr, Mohsen Reham, Rezk Ahmed, Bangay Gabrielle, Rijo Patrícia, Soliman Mona F M, G A Hablas Mohamed, Swidan Khalifa AbdulRazik K, Mohammed Tahseen S, Zoair Mohammad A, Mohamed Abir A Khalil, Abdalrhman Tamer I, Abdel-Aleem Desoky Ahmad M, Mohamed Dalia D, Mohamed Doaa D, Abd El Maksoud Ahmed I, Mohamed Aly F
Department of Bioinformatics, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat 32897, Egypt.
College of Biotechnology, October University for Modern Science and Arts (MSA), University Giza, Giza 11456, Egypt.
ACS Omega. 2024 Feb 16;9(8):8973-8984. doi: 10.1021/acsomega.3c07239. eCollection 2024 Feb 27.
Vitamin C was examined to ameliorate the neurotoxicity of thimerosal (THIM) in an animal model (Wistar albino rats). In our work, oxidative and antioxidative biomarkers such as SOD, LPO, and GSH were investigated at various doses of THIM with or without concurrent vitamin C administration. Furthermore, the adverse effects of THIM on hepatic tissue and cerebral cortex morphology were examined in the absence or presence of associated vitamin C administration. Also, we studied the effect of vitamin C on the metallothionein isoforms (MT-1, MT-2, and MT-3) and using the RT-PCR assay. The results showed that the antioxidant biomarker was reduced as the THIM dose was raised and vice versa. THIM-associated vitamin C reduced the adverse effects of the THIM dose. The computation studies demonstrated that vitamin C has a lower Δ of -4.9 kcal/mol compared to -4.1 kcal/mol for THIM to bind to the MT-2 protein, which demonstrated that vitamin C has a greater ability to bind with MT-2 than THIM. This is due to multiple hydrogen bonds that exist between vitamin C and MT-2 residues Lys31, Gln23, Cys24, and Cys29, and the sodium ion represents key stabilizing interactions. Hydrogen bonds involve electrostatic interactions between hydrogen atom donors (, hydroxyl groups) and acceptors (, carbonyl oxygens). The distances between heavy atoms are typically 2.5-3.5 Å. H-bonds provide directed, high-affinity interactions to anchor the ligand to the binding site. The five H-bonds formed by vitamin C allow it to form a stable complex with MT, while THIM can form two H-bonds with Gln23 and Cys24. This provides less stabilization in the binding pocket, contributing to the lower affinity compared to vitamin C. The histopathological morphologies in hepatic tissue displayed an expansion in the portal tract and the hepatocytes surrounding the portal tract, including apoptosis, binucleation, and karyomegaly. The histopathological morphologies in the brain tissue revealed a significant decrease in the number of Purkinje cells due to THIM toxicity. Interestingly, THIM toxicity was associated with hemorrhage and astrogliosis. Both intracellular and vasogenic edema appeared as the concentrations of THIM rose. Finally, vitamin C ameliorated the adverse effect on the cerebral cortex in Wistar albino rats.
在动物模型（Wistar白化大鼠）中研究了维生素C对硫柳汞（THIM）神经毒性的改善作用。在我们的研究中，研究了不同剂量的THIM在同时给予或不给予维生素C的情况下，氧化和抗氧化生物标志物如超氧化物歧化酶（SOD）、脂质过氧化（LPO）和谷胱甘肽（GSH）的变化。此外，在给予或不给予相关维生素C的情况下，研究了THIM对肝组织和大脑皮层形态的不良影响。同时，我们使用逆转录聚合酶链反应（RT-PCR）检测方法研究了维生素C对金属硫蛋白亚型（MT-1、MT-2和MT-3）的影响。结果表明，随着THIM剂量的增加，抗氧化生物标志物减少，反之亦然。THIM联合维生素C可降低THIM剂量的不良影响。计算研究表明，与THIM结合MT-2蛋白时的-4.1千卡/摩尔相比，维生素C的结合能更低，为-4.9千卡/摩尔，这表明维生素C与MT-2结合的能力比THIM更强。这是由于维生素C与MT-2残基Lys31、Gln23、Cys24和Cys29之间存在多个氢键，并且钠离子代表关键的稳定相互作用。氢键涉及氢原子供体（如羟基）和受体（如羰基氧）之间的静电相互作用。重原子之间的距离通常为2.5 - 3.5埃。氢键提供定向的、高亲和力的相互作用，将配体锚定到结合位点。维生素C形成的五个氢键使其能够与MT形成稳定的复合物，而THIM可以与Gln23和Cys24形成两个氢键。这在结合口袋中提供的稳定性较低，导致与维生素C相比亲和力较低。肝组织的组织病理学形态显示门管区以及门管区周围的肝细胞扩张，包括凋亡、双核化和核肿大。脑组织的组织病理学形态显示由于THIM毒性，浦肯野细胞数量显著减少。有趣的是，THIM毒性与出血和星形胶质细胞增生有关。随着THIM浓度的升高，细胞内水肿和血管源性水肿均出现。最后，维生素C改善了Wistar白化大鼠大脑皮层的不良影响。
