Resatorvid Relieves Breast Cancer Complicated with Depression by Inactivating Hippocampal Microglia Through TLR4/NF-κB/NLRP3 Signaling Pathway

Abstract

Weixu Luo,1,* Yuanshan Han,2,* Pan Meng,1 Qin Yang,3 Hongqing Zhao,1 Jia Ling,1 Yuhong Wang1 1Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Medical Experimental Innovation Center, The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 3Department of Pharmacy, Yueyang Hospital of Traditional Chinese Medicine, Yueyang, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhong WangInstitute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, People’s Republic of ChinaEmail [email protected]: Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD).Methods: The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo.Results: The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood–brain barrier function.Conclusion: In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.Keywords: resatorvid, breast cancer complicated with depression(BCCD), microglia(MG), TLR4/NF-κB/NLRP3 signaling pathway

Keywords

• resatorvid
• breast cancer complicated with depression (bccd)
• microglia (mg)
• tlr4/nf-κb/nlrp3 signaling pathway