Gomaa Asmaa A, Abdallah Dalaal M, El-Abhar Hanan S, El-Mokadem Bassant M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, 6(th) of October City, Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Life Sci. 2024 Dec 15;359:123210. doi: 10.1016/j.lfs.2024.123210. Epub 2024 Oct 31.
The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.
P物质（SP）和神经激肽-1受体（NK-1R）轴在众多病理过程中至关重要，包括炎症、应激反应、痛觉和呕吐。因此，NK-1R阻滞剂阿瑞匹坦被用作化疗中的止吐药，包括在使用多柔比星（DOX）时，但阿瑞匹坦是否也能减轻DOX介导的化疗脑仍有待揭示。在此，我们使用DOX诱导的化疗脑模型仔细研究了阿瑞匹坦的潜在神经保护作用及其潜在机制，将大鼠分为4组（对照组、阿瑞匹坦组、DOX组和DOX + 阿瑞匹坦组）。通过行为测试评估认知缺陷，并通过苏木精-伊红（H&E）染色和甲苯胺蓝染色确定海马结构改变。使用酶联免疫吸附测定（ELISA）、实时定量聚合酶链反应（PCR）、蛋白质印迹法和免疫组织化学方法进行生化检测。阿瑞匹坦改善了认知反应和海马形态，增加了完整神经元的数量。在分子层面，阿瑞匹坦显著降低了海马中SP以及炎症标志物核因子κB（NF-κB）和白细胞介素-1β（IL-1β）的含量。此外，它通过下调裂解的半胱天冬酶-3蛋白表达并抑制丙二醛含量，但提高谷胱甘肽和Bcl-2的含量，表明其抗氧化和抗凋亡能力。阿瑞匹坦还下调了miR-146a的表达，并关闭了内质网（ER）应激级联反应PERK/eIF-2α/ATF-4/CHOP。概括地说，阿瑞匹坦通过减轻炎症、氧化和凋亡反应，部分通过减少SP、ER应激和miR-146a，对DOX介导的化疗脑具有神经保护作用。这些发现不仅强调了阿瑞匹坦作为神经保护剂的潜力，还为化疗脑背后的机制提供了新的理解，从而为癌症患者带来更好的治疗策略。
