Nanjing University of Chinese Medicine, Nanjing, 210023, China; Department of Gastroenterology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, 210014, China.
Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Int Immunopharmacol. 2023 Oct;123:110808. doi: 10.1016/j.intimp.2023.110808. Epub 2023 Aug 16.
Increasing evidence suggests that inflammation appears to play a role in the genesis of depression. Berberine has potent anti-inflammatory effects and potential antidepressant activity, although the mechanism by which it works is yet unclear. Our study aimed to investigate the molecular mechanisms through which berberine treats depression and reduces inflammation.
The CUMS model and behavioral evaluation were utilized in this study to evaluate the efficacy of berberine in the treatment of depression. Berberine's effect on the inflammatory response in CUMS mice was evaluated via ELISA assays and western blotting. Nissl staining was used to observe hippocampal neuronal functional damage. Western blotting, ELISA, ubiquitination tests, and immunoprecipitation were utilized in conjunction with in vitro experiments to study the involvement of Trim65 in the antidepressant effects of berberine.
The results suggest that berberine effectively alleviates depressive symptoms, suppresses the expression of genes associated with the NLRP3 inflammasome (NLRP3, cleaved caspase-1, ASC, GSDMD-N, Pro-IL-1β, IL-1β, Pro-IL-18, and IL-18), and reduces hippocampal neuronal functional damage in CUMS mice. Further studies showed that knockdown of Trim65 reversed the effects of berberine and increased NLRP3 inflammasome activity. Finally, K285, an important site for Trim65 binding to NLRP3, was identified.
Our study describes the mechanism of berberine limiting NLRP3 inflammasome activity by promoting the conjugation of Trim65 to NLRP3 and NLRP3 ubiquitination, and suggests NLRP3 inflammasome activation as a prospective target for treating inflammation-associated disorders such as depression.
越来越多的证据表明，炎症似乎在抑郁症的发生中起作用。小檗碱具有很强的抗炎作用和潜在的抗抑郁活性，但其作用机制尚不清楚。本研究旨在探讨小檗碱治疗抑郁症和减轻炎症的分子机制。
本研究采用 CUMS 模型和行为评估来评估小檗碱治疗抑郁症的疗效。通过 ELISA 检测和 Western blot 来评估小檗碱对 CUMS 小鼠炎症反应的影响。尼氏染色观察海马神经元功能损伤。Western blot、ELISA、泛素化试验和免疫沉淀与体外实验相结合，研究 Trim65 在小檗碱抗抑郁作用中的作用。
结果表明，小檗碱能有效缓解抑郁症状，抑制与 NLRP3 炎性体相关基因的表达（NLRP3、cleaved caspase-1、ASC、GSDMD-N、Pro-IL-1β、IL-1β、Pro-IL-18 和 IL-18），减轻 CUMS 小鼠海马神经元功能损伤。进一步的研究表明，Trim65 的敲低逆转了小檗碱的作用，并增加了 NLRP3 炎性体的活性。最后，确定了 Trim65 与 NLRP3 结合的重要位点 K285。
本研究描述了小檗碱通过促进 Trim65 与 NLRP3 的缀合和 NLRP3 的泛素化来限制 NLRP3 炎性体活性的机制，并提出了 NLRP3 炎性体激活作为治疗与炎症相关疾病（如抑郁症）的潜在靶点。
