AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation  

作　　者：Heyu Yang Yujia Wang Shuqing Zhen Banghua Wang Ming Jiao Ling Liu Dai Li Haili Zhu Min Xie 

机构地区：[1]Xianning Medical College,Hubei University of Science and Technology,Xianning 437100,China [2]Xianning Central Hospital,The First Affiliated Hospital of Hubei University of Science and Technology,Xianning 437100,China [3]Department of Rheumatism,Matang Hospital of Traditional Chinese Medicine,Xianning 437100,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第3期460-471,共12页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(Nos.81971066,81901149,and 32100823);the Research Project of Hubei Provincial Department of Education(No.Q20212804);the Hubei University of Science and Technology Program(Nos.2020TD02,BK202116,and 2020XZ40).

摘　　要：Bone metastasis of cancer cells leads to severe pain by disrupting bone structure and inducing central sensitization.Neuroinflammation in the spinal cord plays a decisive role in the maintenance and development of pain.In the current study,male Sprague-Dawley(SD)rats are used to establish a cancer-induced bone pain(CIBP)model by intratibial injection of MRMT-1 rat breast carcinoma cells.Morphological and behavioral analyses verify the establishment of the CIBP model,which represents bone destruction,spontaneous pain and mechanical hyperalgesia in CIBP rats.Activation of astrocytes marked by upregulated glial fibrillary acidic protein(GFAP)and enhanced production of the proinflammatory cytokine interleukin-1β(IL-1β)are accompanied by increased inflammatory infiltration in the spinal cord of CIBP rats.Furthermore,activation of the NOD-like receptor pyrin domain-containing protein 3(NLRP3)inflammasome is consistent with increased neuroinflammation.Adenosine monophosphateactivated protein kinase(AMPK)activation is involved in attenuating inflammatory pain and neuropathic pain.Intrathecal injection of the AMPK activator AICAR in the lumbar spinal cord reduces dynamin-related protein 1(Drp1)GTPase activity and suppresses NLRP3 inflammasome activation.This effect consequently alleviates pain behaviors in CIBP rats.Cell research on C6 rat glioma cells indicates that AICAR treatment restores IL-1β-induced impairment of mitochondrial membrane potential and elevation of mitochondrial reactive oxygen species(ROS).In summary,our findings indicate that AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation in the spinal cord.

关 键 词：cancer-induced bone pain AMPK AICAR spinal inflammation NLRP3-mediated inflammatory signal mitochondrial dysfunction 

分 类 号：R730.55[医药卫生—肿瘤]