Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, PR China.
Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
Phytomedicine. 2024 Sep;132:155823. doi: 10.1016/j.phymed.2024.155823. Epub 2024 Jun 12.
Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown.
This study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP.
The analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro.
Network pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission.
In conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.
神经损伤引起的神经性疼痛 (NP) 通过触发炎症介质的释放破坏神经可塑性。除了神经炎症导致这种破坏的假说外，穿心莲内酯（Andro）作为一种源自穿心莲的传统生物活性化合物，因其强大的抗炎特性而受到关注。然而，Andro 是否可以通过调节神经炎症来改善 NP 尚不清楚。
本研究旨在探讨 Andro 是否以及如何调节神经炎症并缓解 NP。
使用脊神经结扎 (SNL) 和福尔马林大鼠模型评估 Andro 对 NP 的镇痛作用。采用网络药理学、RNA 测序和实验验证相结合的方法，阐明 Andro 镇痛作用的潜在机制。此外，还采用功能超声、免疫组织化学、定量实时聚合酶链反应 (qPCR)、膜片钳和电子显微镜等多种技术，研究 Andro 影响的特定神经细胞类型、神经功能和神经可塑性变化。
网络药理学分析揭示了 Andro 和疼痛的共同靶点在调节与疼痛相关的炎症方面的关键作用，包括小胶质细胞激活、神经炎症、免疫调节和突触传递。此外，我们证实了 Andro 在缓解疼痛方面优于传统镇痛药加巴喷丁。在这些模型中，观察到 Andro 调节了 SNL 触发的血液动力学反应。转录组分析和分子对接研究表明主要组织相容性复合体 II 类 (MHCII) 基因 (Db1、Da 和 Bb) 参与其中。电子显微镜显示突触超微结构得到改善，电生理研究表明，NP 大鼠给予 Andro 治疗后，谷氨酸能传递选择性减少。系统药理学分析和生物学验证的整合表明，其镇痛机制涉及免疫调节、增强突触可塑性和精确调节兴奋性神经递质传递。
总之，本研究表明，Andro 通过靶向 MHCII 基因，可能成为治疗神经性疼痛的有前途的候选药物。
