Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
Key Laboratory of Basic Research and Clinical Transformation of Perioperative Precision Anesthesia, Jiaxing, China.
Mol Pain. 2024 Jan-Dec;20:17448069241256466. doi: 10.1177/17448069241256466.
Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.
最近的研究表明，周围神经再生过程与神经病理性疼痛密切相关。Toll 样受体 4（TLR4）信号参与了不同类型的疼痛和神经再生。TLR4 诱导髓样分化因子 88 衔接蛋白（MyD88）和 NF-κB 依赖性转录过程在感觉神经元和神经胶质细胞中的募集，产生多种细胞因子，促进疼痛的诱导和持续。我们的研究旨在探讨原花青素通过 TLR4-Myd88 信号通路对疼痛和神经再生的影响。通过建立脊神经结扎（SNL）模型来测量原花青素的镇痛效果。通过显微镜和生长相关蛋白 43（GAP43）染色测量周围神经再生的解剖学测量。利用 Western blot 和/或免疫荧光染色检测 TLR4、髓样分化因子 88 衔接蛋白（MyD88）、离子钙结合衔接分子 1（IBA1）和核因子 kappa-B-p65（NF-κB-p65）的表达，以及星形胶质细胞和小胶质细胞的激活。鞘内给予 TLR4 拮抗剂（LPS-RS-Ultra，LRU），以评估阻断 TLR4 信号对疼痛和神经再生的行为影响。原花青素可减轻机械性痛觉过敏、热痛觉过敏，并显著抑制 SNL 模型中再生神经纤维的数量和髓鞘化程度。与假手术组相比，TLR4、MyD88、IBA1 和 NF-κB-p65 的磷酸化在 SNL 大鼠中上调，原花青素给药后被逆转。此外，原花青素还抑制了脊髓星形胶质细胞和小胶质细胞的激活。TLR4-MyD88 信号的抑制有助于原花青素缓解神经病理性疼痛和减少神经再生。
