Abstract：
BACKGROUND: Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works.
OBJECTIVE: In this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms.
METHODS: APOE-/- mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant.
RESULTS: APOE-/- mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE-/- mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice.
CONCLUSIONS: Our study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.
OBJECTIVE: In this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms.
METHODS: APOE-/- mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant.
RESULTS: APOE-/- mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE-/- mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice.
CONCLUSIONS: Our study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.
摘要：
背景：由于抑郁症的发病机制复杂，抗抑郁治疗仍然不能令人满意。最近的证据表明抑郁症和脂质代谢之间存在联系。柴胡皂苷（SS）在现代药理学中具有抗抑郁和调脂作用。然而,目前尚不清楚调脂是否是SS抗抑郁作用的关键机制以及它是如何起作用的。
目的：在本研究中，我们研究了SS的抗抑郁活性与脂质代谢调节之间的关系，并探索了潜在的机制。
方法：APOE-/-小鼠，结合慢性不可预测的轻度应激(CUMS)模型，通过行为研究SS抗抑郁活性与脂质代谢之间的关系，电生理技术,和非靶向脂质组学。蛋白质印迹,原代细胞培养技术,和激光散斑脑血流成像用于阐明潜在的机制。GraphPadPrism用于统计分析，并且p<0.05被认为具有统计学意义。
结果：APOE-/-小鼠在CUMS中表现出更严重的抑郁样行为和鞘脂代谢失调。SS缓解CUMS引起的抑郁行为和皮质鞘脂代谢紊乱，但对APOE-/-小鼠没有影响。SS通过酸性鞘磷脂酶（AMSase）缓解神经酰胺（Cer）和鞘磷脂（SM）之间的失衡。此外,SS通过鞘脂代谢调节神经元谷氨酸释放，从而减轻CUMS诱导的神经血管偶联抑制（调节代谢型谷氨酸受体和IP3受体），改善抑郁小鼠脑血流量的减少。
结论：我们的研究强调了脂质代谢在SS抗抑郁活性中的作用，并探讨了其潜在机制。这项研究为更好地理解植物药的抗抑郁机制提供了新的见解，同时增加了脂质代谢作为抑郁症治疗策略的可能性。
目的：在本研究中，我们研究了SS的抗抑郁活性与脂质代谢调节之间的关系，并探索了潜在的机制。
方法：APOE-/-小鼠，结合慢性不可预测的轻度应激(CUMS)模型，通过行为研究SS抗抑郁活性与脂质代谢之间的关系，电生理技术,和非靶向脂质组学。蛋白质印迹,原代细胞培养技术,和激光散斑脑血流成像用于阐明潜在的机制。GraphPadPrism用于统计分析，并且p<0.05被认为具有统计学意义。
结果：APOE-/-小鼠在CUMS中表现出更严重的抑郁样行为和鞘脂代谢失调。SS缓解CUMS引起的抑郁行为和皮质鞘脂代谢紊乱，但对APOE-/-小鼠没有影响。SS通过酸性鞘磷脂酶（AMSase）缓解神经酰胺（Cer）和鞘磷脂（SM）之间的失衡。此外,SS通过鞘脂代谢调节神经元谷氨酸释放，从而减轻CUMS诱导的神经血管偶联抑制（调节代谢型谷氨酸受体和IP3受体），改善抑郁小鼠脑血流量的减少。
结论：我们的研究强调了脂质代谢在SS抗抑郁活性中的作用，并探讨了其潜在机制。这项研究为更好地理解植物药的抗抑郁机制提供了新的见解，同时增加了脂质代谢作为抑郁症治疗策略的可能性。
