Research Paper Volume 13, Issue 4 pp 6182—6193
Dexmedetomidine reverses MTX-induced neurotoxicity and inflammation in hippocampal HT22 cell lines via NCOA4-mediated ferritinophagy
- 1 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
- 2 Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430060, China
- 3 Department of Pain, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
- 4 Department of Oral and Maxillofacial Surgery, Laboratory for Tumor Genetics and Regenerative Medicine, The Head and Neurocenter, University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20246, Germany
Received: October 3, 2020 Accepted: January 14, 2021 Published: February 25, 2021https://doi.org/10.18632/aging.202626
How to Cite
Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The incidence of chemotherapy-induced cognitive impairment (CICI) has attracted massive attention. Some studies have demonstrated the neuroprotective effects of dexmedetomidine (DEX). Here, alterations in nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy were investigated as the possible causes of DEX’s neuroprotection of HT22 cells against methotrexate (MTX)-induced neurotoxicity. We used various concentrations of DEX and NCOA4-siRNA to treat MTX-induced neurotoxicity and inflammation in HT22 cells. The biomarkers of HT22 cells viability, apoptosis and inflammatory were tested. The expression of ferritinophagy markers were detected in the HT22 cells by using western blot and Immunofluorescence. We found that 10 and 50 ng/mL of DEX alleviated MTX-induced hippocampal neuronal inflammatory injuries. Meanwhile, DEX also reversed MTX-induced iron and ROS overproduction. Increasing DEX concentrations caused significant falls in the expression of ferritin heavy chain 1 (FTH1). DEX also increased vital ferritinophagy markers, NCOA4 and LC3II. NCOA4-siRNA transfection annulled the neuroprotective effects of DEX on MTX-induced inflammation in HT22 cells. Additionally, because NCOA4-siRNA disrupted ferritinophagy, DEX’s inhibitory impact on MTX-induced iron and ROS overproduction in HT22 cells was also annihilated. DEX weakened MTX-provoked neurontoxicity in HT22 cells, possibly by improving NCOA4-mediated ferritinophagy. Our discoveries present further mechanisms for understanding the protective effects of DEX against MTX-induced cognitive impairment.
DEX: Dexmedetomidine; MTX: methotrexate; CICI: Chemotherapy-induced cognitive impairments1; LDH: lactate dehydrogenase; FTH1: ferritin heavy chain 1; NCOA4: Nuclear receptor coactivator 4; DMEM: Dulbecco's modified Eagle's medium; Ca-AM: Calcein-acetoxymethyl ester; FTL1: ferritin light chain 1; POCD: postoperative cognitive dysfunction; POD: postoperative delirium.