CCR5 antagonist maraviroc alleviates doxorubicin-induced neuroinflammation and neurobehavioral deficiency by regulating NF-κB/NLRP3 signaling in a breast cancer mouse model.

Autor: Wu Y; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China., Che J; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China., Dong J; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China., Zhang X; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China., Deng Y; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China., Chen W; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China., Zhang J; Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China. Electronic address: snapzhang@aliyun.com.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Aug 15; Vol. 254, pp. 109981. Date of Electronic Publication: 2024 May 03.
DOI: 10.1016/j.neuropharm.2024.109981
Abstrakt: The chemotherapeutic agent Doxorubicin (DOX) is known to cause chemotherapy-induced cognitive impairment (CICI). Maraviroc, a potent C-C chemokine receptor 5 (CCR5) antagonist, shows neuroprotective properties, while its role in CICI remains unclear. This study determined the therapeutic potential of maraviroc on CICI. Adult C57BL/6J mice with implanted breast cancer cells received four weekly intraperitoneal injections of saline (Control group), 5 mg/kg DOX (DOX group), 10 mg/kg maraviroc (MVC group), or 5 mg/kg DOX with 10 mg/kg maraviroc (DOX + MVC group). The Morris Water Maze (MWM) was used for neurobehavioural test. Western blot analysis and immunofluorescence were used to evaluate the expressions of inflammatory markers, apoptosis-related proteins, and synaptic-related proteins. The volume and weight of tumor were also evaluated after treatments. DOX treatment significantly increased chemokines (CCL3, CCL4) and inflammatory cytokines (IL-1β, TNF-α) in tumor-bearing mice hippocampus. While maraviroc administration reduced hippocampal proinflammatory factors compared to the DOX group. Furthermore, it also lowered apoptosis markers, restored synaptic proteins levels, and inhibited the NF-κB/NLRP3 pathway. Accordingly, maraviroc treatment significantly improved DOX-induced neurobehavioural impairments as evidenced by an increased number of platform crossings and percentage of target quadrant time in the MWM test. Additionally, when combined with DOX, maraviroc had additional inhibitory effects on tumor growth. These findings suggest that maraviroc can mitigate DOX-induced CICI by suppressing elevated proinflammatory chemokines and cytokines through the NF-κB/NLRP3 pathway, potentially offering an anti-tumor benefit. This research presents a promising therapeutic approach for DOX-induced CICI, enhancing the safety and efficacy of cancer treatments.
Competing Interests: Declaration of competing interest The authors affirm that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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