背景:由于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设之外,穿心莲内酯(Andro),一种来自穿心莲的传统生物活性化合物,因其有效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仍然未知。
目的:本研究旨在探讨Andro是否以及如何调节神经炎症和缓解NP。
方法: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。网络药理学的结合,RNA测序,和实验验证被用来阐明Andro的镇痛作用背后的潜在机制。此外,各种技术,如功能超声,免疫组织化学,定量实时聚合酶链反应(qPCR),膜片钳,和电子显微镜被用来研究特定的神经细胞类型,神经功能,以及受Andro影响的神经可塑性变化。
结果:网络药理学分析揭示了Andro和疼痛的共同靶标在调节疼痛相关炎症中的关键作用,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物,加巴喷丁.在这些模型中,观察到Andro调节由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物II类(MHCII)基因(Db1,Da,和Bb)。电子显微镜显示突触超微结构的改善,电生理研究表明,在接受Andro治疗后,神经病大鼠的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共同证明了疼痛缓解的机制涉及免疫调节,增强突触可塑性,和兴奋性神经传递的精确调节。
结论:结论:这项研究表明Andro,通过靶向MHCII基因,可能作为一个有希望的治疗候选神经性疼痛。
BACKGROUND: 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.
OBJECTIVE: This study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: In conclusion, this study has demonstrated that Andro, by targeting
MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.