Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China; State Key Laboratory of Digestive Health, Beijing, China.
Toxicol Appl Pharmacol. 2024 May;486:116950. doi: 10.1016/j.taap.2024.116950. Epub 2024 May 1.
Antidepressant duloxetine has been shown protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines are the principal mediators of inflammation. Thus, by screening the differential expression of cytokines in the gastric mucosa using cytokine array at 3 h after indomethacin exposure, when the gastric ulcer began to format, we found that indomethacin increased cytokines which promoted inflammation responses, whereas duloxetine decreased pro-inflammatory cytokines increased by indomethacin and increased RANTES expression. RANTES was consistently increased by pretreated with both 5 mg/kg and 20 mg/kg duloxetine at 3 h and 6 h after indomethacin exposure in male rats. Selective blockade of RANTES-CCR5 axis by a functional antagonist Met-RANTES or a CCR5 antagonist maraviroc suppressed the protection of duloxetine. Considering the pharmacologic action of duloxetine on reuptake of monoamine neurotransmitters, we examined the serotonin (5-HT), norepinephrine and dopamine contents in the blood and discovered 20 mg/kg duloxetine increased 5-HT levels in platelet-poor plasma, while treatment with 5-HT promoted expression of RANTES in the gastric mucosa and alleviated the indomethacin-induced gastric injury. Furthermore, duloxetine activated PI3K-AKT-VEGF signaling pathway, which was regulated by RANTES-CCR5, and selective inhibitor of VEGF receptor axitinib blocked the prophylactic effect of duloxetine. Furthermore, duloxetine also protected gastric mucosa from indomethacin in female rats, and RANTES was increased by duloxetine after 6 h after indomethacin exposure too. Together, our results identified the role of cytokines, particularly RANTES, and the underlying mechanisms in gastroprotective effect of duloxetine against indomethacin, which advanced our understanding in inflammatory modulation by monoamine-based antidepressants.
抗抑郁药度洛西汀已被证明对吲哚美辛诱导的胃溃疡具有保护作用，这种保护作用伴随着胃黏膜的炎症。细胞因子是炎症的主要介质。因此，通过在吲哚美辛暴露后 3 小时（即胃溃疡开始形成时）使用细胞因子阵列筛选胃黏膜中细胞因子的差异表达，我们发现吲哚美辛增加了促进炎症反应的细胞因子，而度洛西汀则降低了吲哚美辛增加的促炎细胞因子，并增加了 RANTES 的表达。在雄性大鼠中，吲哚美辛暴露后 3 小时和 6 小时，预先用 5mg/kg 和 20mg/kg 度洛西汀预处理均持续增加 RANTES。RANTES-CCR5 轴的选择性阻断剂 Met-RANTES 或 CCR5 拮抗剂 maraviroc 抑制了度洛西汀的保护作用。考虑到度洛西汀对单胺神经递质再摄取的药理作用，我们检查了血液中的 5-羟色胺（5-HT）、去甲肾上腺素和多巴胺含量，发现 20mg/kg 度洛西汀增加了血小板缺乏血浆中的 5-HT 水平，而 5-HT 处理促进了胃黏膜中 RANTES 的表达，并减轻了吲哚美辛引起的胃损伤。此外，度洛西汀激活了 RANTES-CCR5 调节的 PI3K-AKT-VEGF 信号通路，而 VEGF 受体选择性抑制剂 axitinib 阻断了度洛西汀的预防作用。此外，度洛西汀在雌性大鼠中也能保护胃黏膜免受吲哚美辛的损伤，而且在吲哚美辛暴露后 6 小时，度洛西汀也增加了 RANTES 的表达。总之，我们的研究结果确定了细胞因子，特别是 RANTES 的作用及其在度洛西汀对抗吲哚美辛的胃保护作用中的潜在机制，这加深了我们对基于单胺类抗抑郁药的炎症调节的理解。
