藏红花素通过肠内分泌细胞Olfr558受体激活肠-迷走神经回路快速抗抑郁分子机理

抑郁症危害严重，临床亟需快速高效抗抑郁药。近期研究发现高剂量藏红花素口服给药快速显著抗抑郁，在中枢可调控伏隔核cAMP水平，切断迷走神经抵消其抗抑郁和升高伏隔核cAMP作用，静注给予藏红花素或代谢物藏红花酸无效，提示藏红花素药效依赖于肠道。预实验结果提示藏红花素显著增加肠道嗅觉受体蛋白Olfr558表达，上调肠内容物中果糖、色氨酸和脂肪酸类水平，文献调研发现这些物质有共性作用，即激活肠内分泌细胞。因此创新性的提出科学假说：藏红花素可调控肠道内源性代谢分子，激活肠内分泌细胞，通过肠-迷走神经-脑回路快速抗抑郁。计划通过代谢组学、肠内分泌细胞功能和递质研究明确肠内分泌细胞是藏红花素抗抑郁的肠道靶点；进一步用转基因小鼠，激动剂或抑制剂研究Olfr558受体在肠内分泌细胞激活过程中的作用。阐明藏红花素快速抗抑郁的药效新模式，为转化应用提供研究基础，同时拓展了药物在外周发挥中枢保护作用研究的新思路。

Depression is a common mental disorder, and there is a scarcity of effective clinical drugs. Our study found that oral administration of 300 mg/kg crocin had significant antidepressant effects, increased the level of cAMP in the nucleus accumbens, but the antidepressant effect and the regulation of cAMP were significantly reduced after vagotomy. No such effects were observed by intravenous injection of equivalent crocin or crocetin, suggesting that the antidepressant effect was depend on the gut. The pre-experiment suggested that crocin could increase the expression of Olfr558, and up-regulate the level of fructose, tryptophan and fatty acids in the gut content. Literature study found that there is a commonality of these metabolites, that is activating enteroendocrine cells. Therefore, we propose the hypothesis that crocin could activate enteroendocrine cells through regulating metabolic homeostasis in the gut content, and exert a rapid antidepressant effect through the enteric-vagal-brain neural circuit. This project will confirm that enteroendocrine cells are the intestinal target of crocin through metabolomic study and the function study of enteroendocrine cells. The role of Olfr558 in enteroendocrine cells will be further investigated using transgenic mice, agonists and inhibitors. Clarifying the innovative pharmacodynamic model of crocin’s rapid antidepressant will provide the research basis for transformation and application, and expand the new thoughts of research on central protective effect at peripheral.