Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran.
Phytomedicine. 2023 Oct;119:154989. doi: 10.1016/j.phymed.2023.154989. Epub 2023 Jul 20.
BACKGROUND: Depression is a debilitating condition that affects the mind and the individual's body. The improving effects of saffron on depression and anxiety have long been discussed, with limited information about the molecular mechanism of action. HYPOTHESIS/PURPOSE: Investigating the effect of saffron carotenoids, Crocin and Crocetin, on depression and anxiety in rats by emphasizing some signaling pathways involved. STUDY DESIGN: Depression and anxiety were induced in rats via unpredictable chronic mild stress (UCMS). Then different rat groups were treated with Crocin, Crocetin, Fluoxetine, and vehicle. Behavioral tests were done before and after treatment. METHODS: The serum Serotonin and Corticosterone and the expression of some hippocampal signaling proteins were studied. Furthermore, bioinformatics tools were used to predict the interactions of Crocin/ Crocetin with the Serotonin transporter and NMDA receptor subunit NR2B. Then, the patch-clamp was used to study the interaction of Crocetin with the NMDA receptor. RESULTS: Various behavioral tests confirmed the induction of depression and the improvement of depression by these natural carotenoids. In addition, Crocin/ Crocetin significantly increased the decreased serum Serotonin and reduced the increased serum Corticosterone in the depressed groups. They also increased or caused a trend of increase in the CREB, ERK, BAD, BDNF, p11, and 5-HT1B expression in the hippocampus of the depressed groups. In addition, there were an increase or a trend in p-CREB/CREB, p-ERK /ERK, and p-BAD/BAD ratios in the Crocin/ Crocetin treated depressed groups. However, the NR2B and FOXO3a expression showed a trend of decrease in depressed groups after treatment. The bioinformatics data indicated that Crocin/ Crocetin could bind to the Serotonin transporter (SLC6A4) and NR2B subunit of the NMDA receptor. Both carotenoids bind to the same site as Fluoxetine in the SLC6A4. However, they bound to different sites on the NR2B. So, Crocetin binds to NR2B at the same site as Ifenprodil. But Crocin bound to another site. The whole cell patch-clamp recording on the normal rat hippocampus revealed a significant decrease in the NMDA peak amplitude after Crocetin treatment, indicating its inhibitory effect on this receptor. CONCLUSION: The antidepressant activities of Crocin/ Crocetin are possibly due to their effects on Serotonin and Corticosterone serum concentrations, NR2B expression, and the downstream signaling pathways. Furthermore, these natural carotenoids, like Fluoxetine, induced an increasing tendency in p11 and 5HT1B in depressed rats.
背景：抑郁症是一种影响身心的衰弱性疾病。藏红花对抑郁症和焦虑症的改善作用一直备受关注，但关于其作用机制的信息有限。
假设/目的：通过强调一些相关的信号通路，研究藏红花类胡萝卜素藏红花酸和西红花酸对大鼠抑郁和焦虑的影响。
研究设计：通过不可预测的慢性轻度应激（UCMS）诱导大鼠产生抑郁和焦虑。然后，将不同的大鼠组分别用藏红花酸、西红花酸、氟西汀和载体处理。在治疗前后进行行为测试。
方法：研究血清 5-羟色胺和皮质酮的表达以及一些海马信号蛋白的表达。此外，还使用生物信息学工具预测藏红花酸/西红花酸与 5-羟色胺转运体和 NMDA 受体亚单位 NR2B 的相互作用。然后，使用膜片钳技术研究西红花酸与 NMDA 受体的相互作用。
结果：各种行为测试证实了这些天然类胡萝卜素可诱导抑郁并改善抑郁。此外，藏红花酸/西红花酸显著增加了抑郁组降低的血清 5-羟色胺水平，并降低了升高的血清皮质酮水平。它们还增加或导致抑郁组海马中 CREB、ERK、BAD、BDNF、p11 和 5-HT1B 的表达增加或呈增加趋势。此外，在藏红花酸/西红花酸处理的抑郁组中，p-CREB/CREB、p-ERK/ERK 和 p-BAD/BAD 的比值也呈增加或增加趋势。然而，NR2B 和 FOXO3a 的表达在治疗后呈下降趋势。生物信息学数据表明，藏红花酸/西红花酸可与 5-羟色胺转运体（SLC6A4）和 NMDA 受体的 NR2B 亚基结合。这两种类胡萝卜素都与氟西汀在 SLC6A4 中的相同结合位点结合。然而，它们与 NMDA 受体的不同部位结合。因此，西红花酸与 Ifenprodil 相同的位点与 NR2B 结合。但藏红花酸与另一个位点结合。对正常大鼠海马的全细胞膜片钳记录显示，西红花酸处理后 NMDA 峰幅度明显降低，表明其对该受体具有抑制作用。
结论：藏红花酸/西红花酸的抗抑郁活性可能与其对血清 5-羟色胺和皮质酮浓度、NR2B 表达及下游信号通路的影响有关。此外，这些天然类胡萝卜素，如氟西汀，可诱导抑郁大鼠中 p11 和 5-HT1B 呈上升趋势。
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