Inhibition of spinal ferroptosis-like cell death alleviates hyperalgesia and spontaneous pain in a mouse model of bone cancer pain

Zhuofeng Ding; Xiaoshen Liang; Jian Wang; Zongbin Song; Qulian Guo; Michael K E Schäfer; Changsheng Huang

doi:10.1016/j.redox.2023.102700

Inhibition of spinal ferroptosis-like cell death alleviates hyperalgesia and spontaneous pain in a mouse model of bone cancer pain

Redox Biol. 2023 Jun:62:102700. doi: 10.1016/j.redox.2023.102700. Epub 2023 Apr 12.

Authors

Zhuofeng Ding¹, Xiaoshen Liang¹, Jian Wang¹, Zongbin Song¹, Qulian Guo², Michael K E Schäfer³, Changsheng Huang⁴

Affiliations

¹ Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, 410008, China.
² Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, 410008, China.
³ Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Germany; Focus Program Translational Neurosciences (FTN) and Research Center of Immunotherapy of the Johannes Gutenberg-University Mainz, Germany.
⁴ Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, 410008, China. Electronic address: changsheng.huang@csu.edu.cn.

Abstract

Bone cancer pain (BCP) impairs patients' quality of life. However, the underlying mechanisms are still unclear. This study investigated the role of spinal interneuron death using a pharmacological inhibitor of ferroptosis in a mouse model of BCP. Lewis lung carcinoma cells were inoculated into the femur, resulting in hyperalgesia and spontaneous pain. Biochemical analysis revealed that spinal levels of reactive oxygen species and malondialdehyde were increased, while those of superoxide dismutase were decreased. Histological analysis showed the loss of spinal GAD65+ interneurons and provided ultrastructural evidence of mitochondrial shrinkage. Pharmacologic inhibition of ferroptosis using ferrostatin-1 (FER-1, 10 mg/kg, intraperitoneal for 20 consecutive days) attenuated ferroptosis-associated iron accumulation and lipid peroxidation and alleviated BCP. Furthermore, FER-1 inhibited the pain-associated activation of ERK1/2 and COX-2 expression and prevented the loss of GABAergic interneurons. Moreover, FER-1 improved analgesia by the COX-2 inhibitor Parecoxib. Taken together, this study shows that pharmacological inhibition of ferroptosis-like cell death of spinal interneurons alleviates BCP in mice. The results suggest that ferroptosis is a potential therapeutic target in patients suffering on BCP and possibly other types of pain.

Keywords: BCP; Ferroptosis; GABA; Oxidative stress; Spinal cord.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Neoplasms* / complications
Bone Neoplasms* / drug therapy
Cancer Pain* / drug therapy
Cancer Pain* / etiology
Cell Death
Ferroptosis*
Hyperalgesia / drug therapy
Hyperalgesia / etiology
Mice
Pain
Quality of Life