LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response

Zhao,Jiajia; Yan,Ying; Zhen,Shuqing; Yu,Liangzhu; Ding,Jieqiong; Tang,Qiong; Liu,Ling; Zhu,Haili; Xie,Min

doi:10.3892/ijmm.2023.5245

LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response

Authors:
- Jiajia Zhao
- Ying Yan
- Shuqing Zhen
- Liangzhu Yu
- Jieqiong Ding
- Qiong Tang
- Ling Liu
- Haili Zhu
- Min Xie
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Affiliations: Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China, Xishui Hospital Affiliated to Hubei University of Science and Technology, Huanggang, Hubei 438299, P.R. China, Matang Hospital of Traditional Chinese Medicine, Xianning, Hubei 437020, P.R. China
Published online on: April 7, 2023 https://doi.org/10.3892/ijmm.2023.5245
Article Number: 42
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bone cancer pain (BCP) is mainly caused by bone metastasis and markedly impairs the functional capacity and daily functions of patients. Neuroinflammation plays a pivotal role in the pathogenesis and maintenance of chronic pain. Oxidative stress in the mitochondria is a key contributor to neuroinflammation and neuropathic pain. Herein, a rat model of BCP was established which was characterized by bone destruction, pain hypersensitivity and motor disability. In the spinal cord, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) signaling was activated, and the inflammatory response and mitochondrial dysfunction were also observed. The intrathecal injection of LY294002, a selective inhibitor of PI3K/Akt signaling, decreased mechanical pain sensitivity, suppressed spontaneous pain and recovered the motor coordination of rats with BCP. Second, LY294002 treatment blocked spinal inflammation by reducing astrocytic activation and downregulating the expression levels of inflammatory factors, such as NF‑κB, IL‑1β and TNF‑α. Moreover, LY294002 treatment recovered mitochondrial function by activating the manganese superoxide dismutase enzyme, increasing NADH:ubiquinone oxidoreductase subunit B11 expression, and decreasing BAX and dihydroorotate dehydrogenase expression. LY294002 treatment also increased the mitochondrial membrane potential and decreased the mitochondrial reactive oxygen species levels in C6 cells. On the whole, the results of the present study suggest that the inhibition of PI3K/Akt signaling by LY294002 restores mitochondrial function, suppresses spinal inflammation and alleviates BCP.

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