Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway
Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway
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DOI：
10.1007/s12011-022-03142-5
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发表时间：
2022-02
影响因子：
3.9
通讯作者：
Can-can Zhou;Yu-Qiong He;Yu Qiu;Chenxu Ni;Fu-Ming Shen;Dong-Jie Li
中科院分区：
文献类型：
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作者：
Can-can Zhou;Yu-Qiong He;Yu Qiu;Chenxu Ni;Fu-Ming Shen;Dong-Jie Li
索拉非尼是一种多种激酶抑制剂，广泛用于癌症患者。最近，临床研究强调了认知缺陷与索拉非尼暴露之间的关系。据报道，体内丰富的锌具有神经保护作用。然而，锌补充剂对索拉非尼诱导的认知障碍的影响仍不清楚。在目前的研究中，我们证实了用索拉非尼刺激的小鼠表现出认知障碍的特征。然而，锌处理有效地改善了这些变化。组织病理学染色也显示，锌能显著减轻索拉非尼引起的海马微结构和超微结构损伤。同时，锌在体内和体外均显著降低索拉非尼诱导的ROS生成和神经元细胞凋亡。此外，我们还通过NAC或特异性JNK激活剂大霉素处理SH-SY5Y细胞，研究锌是否通过ROS/JNK途径保护索拉非尼诱导的神经元细胞凋亡。结果表明，NAC对索拉非尼激发的SH-SY5Y细胞具有与锌相同的保护作用，而大霉素激活JNK可部分消除锌的保护作用。总之，本研究表明，氧化应激和JNK通路的抑制可能有助于锌对索拉非尼引起的体内和体外认知损伤的保护作用。
Sorafenib, a multiple kinase inhibitor, is widely used in cancer patients. Recently, clinical studies highlighted the relationship between cognitive deficits and sorafenib exposure. Zinc abundant in the body has been reported to exert neuroprotective activities. However, the effects of zinc supplementation on sorafenib-induced cognitive impairment are still unknown. In the current study, we verified that mice challenged with sorafenib displayed characteristic features of cognitive impairment. However, zinc treatment effectively improved these changes. Histopathological staining also showed that zinc significantly alleviated hippocampal microstructural and ultrastructural damages induced by sorafenib. Meanwhile, zinc significantly reduced sorafenib-induced ROS production and neuronal cells apoptosis in vivo and vitro. Additionally, we also investigated whether zinc protected against sorafenib-induced neuronal cells apoptosis via ROS/JNK pathway through treating SH-SY5Y cells with the NAC or the specific JNK activator anisomycin. The results indicated that NAC performed the same protective effects as zinc in sorafenib-challenged SH-SY5Y cells and activation of JNK by anisomycin partly abolished the protective effects of zinc. Collectively, the present study suggested that inhibition of oxidative stress and the JNK pathway might contribute to the protective effects of zinc against sorafenib-caused cognitive impairment in vivo and vitro.