Ruxolitinib improves the inflammatory microenvironment,restores glutamate homeostasis,and promotes functional recovery after spinal cord injury  

作　　者：Jiang Cao Xiao Yu Jingcheng Liu Jiaju Fu Binyu Wang Chaoqin Wu Sheng Zhang Hongtao Chen Zi Wang Yinyang Xu Tao Sui Jie Chang Xiaojian Cao 

机构地区：[1]Department of Orthopedics,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China [2]Department of Trauma Surgery,Subei People’s Hospital of Jiangsu,Clinical Medical College of Yangzhou University,Yangzhou,Jiangsu Province,China [3]Department of Orthopedics,Zhongda Hospital,Southeast University,Nanjing,Jiangsu Province,China [4]Department of Orthopedic Surgery,Nanjing Drum Tower Hospital,The Affiliated Hospital of Medical School of Nanjing University,Nanjing,Jiangsu Province,China

出　　处：《Neural Regeneration Research》2024年第11期2499-2512,共14页中国神经再生研究（英文版）

基　　金：supported by the National Natural Science Foundation of China,No.82272484(to XC).

摘　　要：The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.

关 键 词：astrocytes EAAT2 EXCITOTOXICITY glutamate homeostasis JAK-STAT pathway locomotor function NEUROTOXICITY RUXOLITINIB spinal cord injury transcriptome analysis 

分 类 号：R651.2[医药卫生—外科学]