Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao.
Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 1):118787. doi: 10.1016/j.jep.2024.118787. Epub 2024 Sep 6.
Cognitive dysfunction associated with diabetes, known as diabetic encephalopathy (DE), is a grave neurodegenerative condition triggered by diabetes, and persistent inflammation plays a vital role in its development. The renowned traditional Chinese medicine Huang-Lian-Jie-Du Decoction (HLJDD) is clinically proven to manage diabetes mellitus and Alzheimer's disease and is famous for its heat-clearing and detoxifying effects. However, the underlying mechanisms through which HLJDD affects DE remain to be elucidated.
To explore the beneficial effects of HLJDD on improving cognitive dysfunction in DE mice.
A diabetic mouse was established through a high-fat diet and subsequent administration of streptozotocin over five consecutive days. After the animals were confirmed to have diabetes, they were treated with HLJDD. After oral administration of HLJDD or metformin for 14 weeks, behavioral tests were used to assess their cognitive capacity. Biochemical analyses were then performed to detect levels of glucose metabolism, followed by histological analyses to assess pathological damage. Furthermore, AGEs/RAGE/NF-κB axis related proteins were detected by Western blot or immunofluorescence techniques. An advanced UPLC-Q-Orbitrap HRMS/MS analytical technique utilizing a chemical derivatization strategy was employed for comprehensive metabolic profiling of carbonyl compounds in the plasma of DE mice.
Pharmacological assessment revealed that HLJDD effectively mitigated cognitive dysfunction, normalized glucose metabolic imbalances, and repaired neuronal damage in DE mice. It reduced neuroinflammation by attenuating carbonyl stress, deactivating astrocytes and microglia, and preserving dopaminergic neurons. Additionally, metabolomics analysis revealed 18 carbonyl compounds with marked disparities between DE and control mice, with 12 metabolites approaching normal levels post-HLJDD intervention. Further investigations showed that HLJDD regulated inflammation and pyroptosis through suppressing AGEs/RAGE/NF-κB pathways.
Our study indicated that HLJDD could ameliorate carbonyl stress via the regulation of carbonyl compound metabolism profiling, and inhibiting the AGEs/RAGE/NF-κB pathway, thereby alleviating inflammation and pyroptosis to exert beneficial effects on DE.
与糖尿病相关的认知功能障碍，即糖尿病性脑病 (DE)，是一种由糖尿病引发的严重神经退行性疾病，持续的炎症在其发展中起着至关重要的作用。著名的中药黄连解毒汤 (HLJDD) 已被临床证明可用于治疗糖尿病和阿尔茨海默病，以其清热解毒的功效而闻名。然而，HLJDD 影响 DE 的潜在机制仍有待阐明。
探讨 HLJDD 改善 DE 小鼠认知功能障碍的有益作用。
通过连续 5 天给予高脂肪饮食和链脲佐菌素，建立糖尿病小鼠模型。动物确诊糖尿病后，给予 HLJDD 治疗。经口给予 HLJDD 或二甲双胍 14 周后，进行行为测试评估其认知能力。然后进行生化分析以检测葡萄糖代谢水平，接着进行组织学分析以评估病理损伤。此外，通过 Western blot 或免疫荧光技术检测 AGEs/RAGE/NF-κB 轴相关蛋白。采用基于化学衍生化策略的先进 UPLC-Q-Orbitrap HRMS/MS 分析技术，对 DE 小鼠血浆中的羰基化合物进行全面代谢谱分析。
药效学评估表明，HLJDD 可有效缓解 DE 小鼠的认知功能障碍，使葡萄糖代谢失衡正常化，并修复神经元损伤。它通过减轻羰基应激、使星形胶质细胞和小胶质细胞失活以及保护多巴胺能神经元来减轻神经炎症。此外，代谢组学分析显示，DE 组和对照组之间有 18 种羰基化合物存在明显差异，经 HLJDD 干预后 12 种代谢物接近正常水平。进一步研究表明，HLJDD 通过抑制 AGEs/RAGE/NF-κB 通路调节炎症和细胞焦亡。
本研究表明，HLJDD 可以通过调节羰基化合物代谢谱来减轻羰基应激，抑制 AGEs/RAGE/NF-κB 通路，从而减轻炎症和细胞焦亡，对 DE 发挥有益作用。
