Chai Yihui, He Siyu, Liang Dayi, Gu Chunsong, Gong Qian, Long Ling, Chen Peng, Wang Long
Basic Medical School, Guizhou University of Traditional Chinese Medicine, Guiyang, 550000, China.
School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
Heliyon. 2024 Aug 10;10(16):e35970. doi: 10.1016/j.heliyon.2024.e35970. eCollection 2024 Aug 30.
Neuropathic pain (NeP) is a condition charactesized by nervous system injury or dysfunction that affects a significant portion of the population. Current treatments are ineffective, highlighting the need for novel therapeutic approaches. Mahuang Fuzi Xixin decoction (MFXD) has shown promise for treating pain conditions in clinical practice; however, its potential against NeP and the underlying mechanisms remain unclear. This study identified 35 compounds in MFXD using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). The analgesic effects of MFXD on chronic constriction injury (CCI) rats were evaluated through the detection of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). The analgesic effects of MFXD in rats with chronic constriction injury (CCI) were evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Low-dose MFXD (L-MFXD) group (4.8 g/kg) and high-dose MFXD (H-MFXD) group (9.6 g/kg) exhibited significantly higher MWT and TWL values than the CCI group on days 11 and 15 post-CCI surgery, substantiating the remarkable analgesic efficacy of MFXD. Network pharmacology analysis identified 58 key targets enriched in pathways such as long-term potentiation (LTP) and glutamatergic synapse. The MCODE algorithm further identified core targets with significant enrichment in LTP. Molecular docking revealed that mesaconitine, rosmarinic acid, and delgrandine from MFXD exhibited high binding affinity with NMDAR2B (-11 kcal/mol), CaMKIIα (-14.3 kcal/mol), and ERK (-10.8 kcal/mol). Western blot and immunofluorescence confirmed that H-MFXD significantly suppressed the phosphorylation levels of NMDAR2B, CaMKIIα, ERK, and CREB in the spinal cord tissue of CCI rats. In conclusion, this study demonstrates that MFXD possesses potent analgesic effects on NeP by suppressing the NMDAR2B/CaMKIIα/ERK/CREB signalling pathway. This study unlocks a path toward potentially revolutionising NeP treatment with MFXD, encouraging further research and clinical development.
神经病理性疼痛（NeP）是一种以神经系统损伤或功能障碍为特征的疾病，影响着相当一部分人群。目前的治疗方法效果不佳，凸显了对新型治疗方法的需求。麻黄附子细辛汤（MFXD）在临床实践中已显示出治疗疼痛性疾病的潜力；然而，其对神经病理性疼痛的潜在作用及潜在机制仍不清楚。本研究采用超高效液相色谱-高分辨率质谱联用技术（UHPLC-HRMS）鉴定出MFXD中的35种化合物。通过检测机械缩足阈值（MWT）和热缩足潜伏期（TWL），评估MFXD对慢性压迫性损伤（CCI）大鼠的镇痛作用。通过测量机械缩足阈值（MWT）和热缩足潜伏期（TWL），评估MFXD对慢性压迫性损伤（CCI）大鼠的镇痛作用。低剂量MFXD（L-MFXD）组（4.8 g/kg）和高剂量MFXD（H-MFXD）组（9.6 g/kg）在CCI手术后第11天和第15天的MWT和TWL值显著高于CCI组，证实了MFXD显著的镇痛效果。网络药理学分析确定了58个关键靶点，这些靶点富集于长时程增强（LTP）和谷氨酸能突触等通路。MCODE算法进一步确定了在LTP中显著富集的核心靶点。分子对接显示，MFXD中的中乌头碱、迷迭香酸和去甲乌药碱与NMDAR2B（-11 kcal/mol）、CaMKIIα（-14.3 kcal/mol）和ERK（-10.8 kcal/mol）表现出高结合亲和力。蛋白质免疫印迹法和免疫荧光法证实，H-MFXD显著抑制了CCI大鼠脊髓组织中NMDAR2B、CaMKIIα、ERK和CREB的磷酸化水平。总之，本研究表明MFXD通过抑制NMDAR2B/CaMKIIα/ERK/CREB信号通路对神经病理性疼痛具有强大的镇痛作用。本研究为用MFXD彻底改变神经病理性疼痛的治疗开辟了一条道路，鼓励进一步的研究和临床开发。
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