Research Paper Volume 15, Issue 21 pp 12537—12550
Cyclosporin A-mediated translocation of HuR improves MTX-induced cognitive impairment in a mouse model via NCOA4-mediated ferritinophagy
- 1 Department of Pain, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People’s Republic of China
- 2 Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, People’s Republic of China
Received: July 12, 2023 Accepted: October 12, 2023 Published: November 9, 2023
https://doi.org/10.18632/aging.205195How to Cite
Copyright: © 2023 Ding et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Chemotherapy-induced cognitive impairment (CICI) is a subject that requires critical solutions in neuroscience and oncology. However, its potential mechanism of action remains ambiguous. The aim of this study was to investigate the vital role of HuR in the neuroprotection of cyclosporin A (CsA) during methotrexate (MTX)-induced cognitive impairment.
A series of Hu-antigen R (HuR) gain and loss experiments were used to examine cyclosporin A (CsA)-mediated translocation of HuR’s ability to improve MTX-induced cognitive impairment through NCOA4-mediated ferritinophagy in vitro and in vivo.
Obtained results show that the administration of CsA alleviated MTX-induced cognitive impairment in mice. The presence of MTX promoted the shuttling of HuR from the cytoplasm to the nucleus, whereas treatment with CsA increased cytoplasmic HuR expression levels and the levels of ferritinophagy-related proteins, such as NCOA4 and LC3II, compared to the MTX group. However, applying KH-3, an inhibitor of HuR, reversed CsA’s impact on the expression of ferritinophagy-related proteins in the hippocampus and in vitro. Also, treatment with CsA attenuated microglial activation by altering Iba-1 expression and decreased TNF-α and IL-1β levels in mice hippocampi. Moreover, KH-3 neutralized CsA’s effects on the expression of both Iba-1 and HuR in vivo and in vitro.
In summary, CsA was confirmed to have a neuroprotective role in CICI. Its possible underlying mechanisms may be involved in the translocation of HuR. Mediating the translocation of HuR during CICI could mitigate neruoinflammation and neuronal apoptosis via NCOA4-mediated ferritinophagy and, thus, alleviate cognitive impairment in mice with CICI.