Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China; School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Department of Gastroenterology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, 210014, China.
J Ethnopharmacol. 2023 Aug 10;312:116487. doi: 10.1016/j.jep.2023.116487. Epub 2023 Apr 12.
Zuojinwan (ZJW) is a traditional Chinese medicine compound, which is often used clinically to treat gastritis and has anti-inflammatory activity. It was found that ZJW is involved in suppressing the expression of inflammatory factors, and neuroinflammation is thought to be associated with the development of depression.
In this study, we investigated whether ZJW could exert antidepressant effects by regulating MyD88 ubiquitination in depressed mice and attempted to elucidate the possible mechanisms.
Six active compounds of Zuojinwan (ZJW) were identified by HPLC. Then, the effects of ZJW on depression-like behavior in mice were investigated by constructing a chronic unpredictable mild stimulation (CUMS) mouse model. Meanwhile, the effect of ZJW on hippocampal neurons was investigated by Nissl staining. In addition, western blotting, PCR, ELISA, co-immunoprecipitation and immunostaining were used to explore whether ZJW could inhibit neuroinflammation through SPOP/MyD88/NF-κB pathway and thus produce antidepressant effects. Finally, we constructed the AAV-Sh-SPOP virus vector to silence SPOP and verify the mechanism of ZJW's antidepressant action.
ZJW could dramatically ameliorate the depressive behavior induced by CUMS stimulation and alleviate hippocampal neuronal damage. CUMS stimulation resulted in decreased SPOP expression, impaired MyD88 ubiquitination, and activation of downstream NF-κB signaling, which could be reversed by ZJW. In addition, ZJW could significantly ameliorate the abnormal activation of microglia, and the excessive levels of pro-inflammatory factors were inhibited. By blocking the expression of SPOP, we found that ZJW exerted anti-inflammatory and antidepressant effects mainly by promoting the ubiquitination of MyD88 and inhibiting the activation of downstream inflammatory signals.
In conclusion, ZJW possesses alleviating effects on depression induced by CUMS stimulation. ZJW can inhibit neuroinflammation and improve neuroinflammation-induced depression-like behaviors through SPOP/MyD88/NF-κB pathway.
左金丸（ZJW）是一种中药复方，临床上常用于治疗胃炎，具有抗炎活性。研究发现，ZJW 参与抑制炎症因子的表达，而神经炎症被认为与抑郁症的发展有关。
本研究通过构建慢性不可预测轻度刺激（CUMS）小鼠模型，探讨 ZJW 是否通过调节抑郁小鼠中的 MyD88 泛素化来发挥抗抑郁作用，并试图阐明其可能的机制。
通过高效液相色谱法鉴定出左金丸的 6 种活性化合物。然后，通过构建慢性不可预测轻度刺激（CUMS）小鼠模型来研究 ZJW 对小鼠抑郁样行为的影响。同时，通过尼氏染色研究 ZJW 对海马神经元的影响。此外，采用 Western blot、PCR、ELISA、免疫共沉淀和免疫染色法探讨 ZJW 是否通过 SPOP/MyD88/NF-κB 通路抑制神经炎症，从而产生抗抑郁作用。最后，我们构建了 AAV-Sh-SPOP 病毒载体来沉默 SPOP，并验证 ZJW 抗抑郁作用的机制。
ZJW 可显著改善 CUMS 刺激诱导的抑郁行为，并减轻海马神经元损伤。CUMS 刺激导致 SPOP 表达降低，MyD88 泛素化受损，下游 NF-κB 信号激活，而 ZJW 可逆转这些变化。此外，ZJW 可显著改善小胶质细胞的异常激活，抑制促炎因子的过度水平。通过阻断 SPOP 的表达，我们发现 ZJW 主要通过促进 MyD88 的泛素化和抑制下游炎症信号的激活来发挥抗炎和抗抑郁作用。
综上所述，ZJW 对 CUMS 刺激诱导的抑郁具有缓解作用。ZJW 可通过 SPOP/MyD88/NF-κB 通路抑制神经炎症，改善神经炎症诱导的抑郁样行为。
