Sodium aescinate alleviates neuropathic pain through suppressing OGT-mediated O-GlcNAc modification of TLR3 to inactivate MAPK signaling pathway

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2024-09-11 DOI:10.1016/j.brainresbull.2024.111077

Rong Chen , Jiantao Hu , Yang Zhang , Yang Liu , Liujian Cao , Fan He , Qin Wang , Ying Chen , Shengwei Zhang , Songjiang Tang , Baojun Min

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Abstract

Neuropathic pain results from damage to nerves or the brain, and is characterized by symptoms such as allodynia, spontaneous pain, and hyperalgesia. The causes of this type of pain are intricate, which can make it difficult to treat. Sodium aescinate (SA), a natural extract from horse chestnut tree seeds, has been shown to act as a neuroprotector by inhibiting microglia activation. This study aims to explore the therapeutic potential of SA for neuropathic pain and the molecular mechanisms regulated by SA treatment. Through in vivo animal models and experiments, we found that SA treatment significantly reduced mechanical allodynia and heat hyperalgesia in neuropathic pain models. Additionally, SA inhibited O-GlcNAc-transferase (OGT)-induced O-GlcNAcylation (O-GlcNAc) modification in neuropathic pain mice. OGT overexpression could impede the therapeutic effects of SA on neuropathic pain. Further investigation revealed that Toll-like receptor 3 (TLR3), stabilized by OGT-induced O-GlcNAc modification, could activate the Mitogen activated protein kinase (MAPK) signaling pathway. Further in vivo experiments demonstrated that TLR3-mediated p38 mitogen-activated protein kinase (p38MAPK) activation is involved in SA-mediated relief of neuropathic pain. In conclusion, this study uncovers a novel molecular pathway deactivated by SA treatment in neuropathic pain.

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羊栖菜酸钠通过抑制 TLR3 的 OGT 介导的 O-GlcNAc 修饰，使 MAPK 信号通路失活，从而缓解神经性疼痛

神经病理性疼痛由神经或大脑受损引起，以异痛症、自发性疼痛和痛觉过敏等症状为特征。这种疼痛的原因错综复杂，因此很难治疗。从七叶树种子中提取的天然提取物栎氨酸钠（SA）已被证明可抑制小胶质细胞的活化，从而起到保护神经的作用。本研究旨在探索 SA 对神经病理性疼痛的治疗潜力以及 SA 治疗调控的分子机制。通过体内动物模型和实验，我们发现 SA 治疗可显著减轻神经病理性疼痛模型中的机械异感和热痛。此外，SA还能抑制O-GlcNAc-转移酶（OGT）诱导的神经病理性疼痛小鼠的O-GlcNAc（O-GlcNAc）修饰。OGT 过度表达会阻碍 SA 对神经病理性疼痛的治疗效果。进一步研究发现，通过 OGT 诱导的 O-GlcNAc 修饰稳定的 Toll 样受体 3（TLR3）可激活丝裂原活化蛋白激酶（MAPK）信号通路。进一步的体内实验证明，TLR3 介导的 p38 丝裂原活化蛋白激酶（p38MAPK）激活参与了 SA 介导的神经病理性疼痛缓解。总之，本研究发现了一种新型分子通路，通过 SA 治疗神经病理性疼痛可使其失活。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.