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Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway

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Abstract

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.

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Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

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Funding

This work was supported by the grants from National Natural Science Foundation of China (81971306, 82003638), Shanghai Talent Development Fund (2020091), Shanghai “Rising Stars of Medical Talent” Youth Development Program-Youth Medical Talents-Clinical Pharmacist Program [SHWRS(2020)_087], Tongji University-Fundamental Research Funds for the Central Universities (22120210560), Shanghai Sailing Program (NO. 20YF1437600), and PangDeng Program of Shanghai Tenth People’s Hospital (2021SYPDRC037).

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  1. Can-Can Zhou and Yu-Qiong He are contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Can-Can Zhou, Yu-Shuang Qiu, Chen-Xu Ni, Fu-Ming Shen & Dong-Jie Li

  2. Institute of Chinese Materia Madica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Yu-Qiong He

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Dong-Jie Li contributed to the supervision, methodology and original draft and wrote the paper. Fu-Ming Shen was involved in the supervision, designed and wrote the paper. Chen-Xu Ni improved original draft. Yu-Shuang Qiu contributed to the formal analysis and wrote the paper. Yu-Qiong He performed the experiments and data curation. Can-Can Zhou performed the experiments and data curation and wrote the paper. All authors have read and approved the final version of the submitted manuscript.

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Zhou, CC., He, YQ., Qiu, YS. et al. Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway. Biol Trace Elem Res 201, 324–337 (2023). https://doi.org/10.1007/s12011-022-03142-5

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