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.
Eur J Pharmacol. 2020 Jun 5;876:173058. doi: 10.1016/j.ejphar.2020.173058. Epub 2020 Mar 1.
Multiple kinds of monoamine-based antidepressants have been shown prophylactic effects in experimentally induced gastric ulcer. The loss of redox homeostasis plays a principle role in the development of peptic mucosal damage. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are one of the most important sources of reactive oxygen species within the gastrointestinal tract. It is unclear whether there are some common NADPH oxidases modulated by monoamine-based antidepressants in different gastric mucosal damage models. We explored the effects of selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine on the reactive oxygen species production and antioxidant capacity in the gastric mucosa of water immersion restraint (WIRS) or indomethacin treated rats, and examined the role of NADPH oxidases in the protective effects. Pretreated duloxetine prevented the increase of gastric mucosal NADPH oxidase activity and NADPH oxidase inhibitor apocynin dose-dependently protected gastric mucosa from damage by the two factors. Furthermore, dual oxidase 2 (DUOX2) and NADPH oxidase4 (NOX4) are involved in the protective effects of duloxetine in both models. We then examined NADPH oxidases expression modulated by the other monoamine-based antidepressants including selective serotonin reuptake inhibitor (SSRIs) fluoxetine, tricyclic agent (TCAs) amitriptyline and monoamine oxidase inhibitor (MAOs) moclobemide in the two models, and all the three antidepressants reduced the DUOX2 expression in the gastric mucosa. So DUOX2 was a common modulator in the preventive effects of all the monoamine-based antidepressants on WIRS- and indomethacin-induced gastric lesion. Our work provided a peripheral joint molecular target for monoamine modulatory antidepressants, which may be helpful to reveal the mechanisms of this kind of drugs more than monoamine regulation.
多种单胺类抗抑郁药已被证明具有实验性诱导胃溃疡的预防作用。氧化还原平衡的丧失在消化性黏膜损伤的发展中起着重要作用。烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶是胃肠道内活性氧的最重要来源之一。目前尚不清楚单胺类抗抑郁药是否在不同的胃黏膜损伤模型中调节一些共同的 NADPH 氧化酶。我们探讨了选择性 5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRI）度洛西汀对水浸束缚（WIRS）或吲哚美辛处理大鼠胃黏膜活性氧生成和抗氧化能力的影响，并研究了 NADPH 氧化酶在保护作用中的作用。预先给予度洛西汀可防止胃黏膜 NADPH 氧化酶活性增加，NADPH 氧化酶抑制剂 apocynin 呈剂量依赖性地保护胃黏膜免受两种因素的损伤。此外，双氧化酶 2（DUOX2）和 NADPH 氧化酶 4（NOX4）参与了度洛西汀在两种模型中的保护作用。然后，我们检测了其他单胺类抗抑郁药，包括选择性 5-羟色胺再摄取抑制剂（SSRIs）氟西汀、三环抗抑郁药（TCAs）阿米替林和单胺氧化酶抑制剂（MAOIs）吗氯贝胺在两种模型中对 NADPH 氧化酶表达的调节，所有三种抗抑郁药均降低了胃黏膜中的 DUOX2 表达。因此，DUOX2 是单胺类抗抑郁药预防 WIRS 和吲哚美辛诱导的胃损伤的共同调节因子。我们的工作为单胺调节抗抑郁药的外周联合分子靶点提供了依据，这可能有助于揭示这类药物的作用机制，而不仅仅是单胺调节。
