College of Pharmacy, Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
College of Pharmacy, Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750004, China; Ningxia Regional Characteristic Traditional Chinese Medicine Collaborative Innovation Center Co-constructed by the Province and Ministry, Ningxia Engineering and Technology Research Center for Modernization of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, China.
Int Immunopharmacol. 2023 May;118:110043. doi: 10.1016/j.intimp.2023.110043. Epub 2023 Mar 23.
Saikosaponin C (SSc) increases the expression of synaptic proteins and has a unexplored role in the prevention of AD and other neurodegeneration in humans. Therefore, we hypothesized that SSc has the potential to relief of depressive symptoms. Here, our study assessed the role of SSc on depression-like behaviors caused by a chronic social defeat stress (CSDS) in mice and explored the underlying mechanisms.
Behavioral tests were conducted to verify the efficacy of SSC in treating depression-like behavior in mice. The levels of IL-6, TNF-α and IL-1β in brain tissue and BV2 cells were determined by ELISA. The effect of SSc on dendritic spine density was determined by Golgi staining. The percentage of monocytes in peripheral blood was measured using flow cytometry. The levels of STAT3 and DNMT1 under the influence of SSc were assessed by immunofluorescence. Protein expression of DNMT1, DNMT3a, DNMT3b, p-STAT3 and STAT3 in brain and BV2 cells was studied by Western blot. OE-DNMT1 was induced in the experiment to verify the inhibitory effect of DNMT1 on IL-6 methylation in SSC. Luciferase was used to detect SSC specific fragments affecting IL-6 methylation.
SSC treatment significantly alleviated depressive-like behavior, inhibited the levels of inflammatory cytokines including IL-6, IL-1β and TNF-α, increased dendritic spine density and promoted synaptic plasticity in mice. SSC downregulated IL-6, STAT3 and DNMT1 expression in vivo and in vitro. SSC also decreased the percentage of monocytes in peripheral blood and suppressed neuroinflammation in mice. Overexpression of DNMT1 by shRNA abolished the inhibitory effect of SSc on IL-6 methylation.
This study showed that SSc reduced IL6 methylation by inhibiting DNMT1 protein, induced a decrease in IL6 expression, promoted synaptic plasticity, and attenuated CSDS-induced depression-like behavior.
柴胡皂甙 C（SSc）可增加突触蛋白的表达，并在预防 AD 和其他人类神经退行性疾病方面具有尚未探索的作用。因此，我们假设 SSc 有潜力缓解抑郁症状。在这里，我们的研究评估了 SSc 在慢性社交挫败应激（CSDS）引起的小鼠抑郁样行为中的作用，并探讨了其潜在机制。
进行行为测试以验证 SSc 在治疗小鼠抑郁样行为中的功效。通过 ELISA 测定脑组织和 BV2 细胞中 IL-6、TNF-α 和 IL-1β 的水平。通过高尔基染色确定 SSc 对树突棘密度的影响。使用流式细胞术测量外周血中单核细胞的百分比。通过免疫荧光评估 SSc 影响下 STAT3 和 DNMT1 的水平。通过 Western blot 研究脑和 BV2 细胞中 DNMT1、DNMT3a、DNMT3b、p-STAT3 和 STAT3 的蛋白表达。在实验中诱导 OE-DNMT1 以验证 DNMT1 对 SSC 中 IL-6 甲基化的抑制作用。使用荧光素酶检测 SSC 影响 IL-6 甲基化的特定片段。
SSc 治疗可显著缓解抑郁样行为，抑制包括 IL-6、IL-1β 和 TNF-α 在内的炎症细胞因子水平，增加树突棘密度并促进小鼠突触可塑性。SSc 在体内和体外下调 IL-6、STAT3 和 DNMT1 的表达。SSc 还降低了外周血中单核细胞的百分比并抑制了小鼠的神经炎症。通过 shRNA 过表达 DNMT1 可消除 SSc 对 IL-6 甲基化的抑制作用。
本研究表明，SSc 通过抑制 DNMT1 蛋白减少 IL6 甲基化，导致 IL6 表达降低，促进突触可塑性，并减轻 CSDS 引起的抑郁样行为。
