Mahdianipur Saeed, Maralani Mahafarin, Mohammadi Saeed, Khandoozi Seyed Reza, Jaefari Afifeh, Davoodi Homa
Immunology, Golestan University of Medical Sciences, Gorgan, IRN.
Oncology, Atlantic Cancer Research Institute, Dr. Georges-L.Dumont University Hospital Centre, Moncton, CAN.
Cureus. 2024 Oct 5;16(10):e70912. doi: 10.7759/cureus.70912. eCollection 2024 Oct.
Background Serotonin (5-HT) is a neurotransmitter with extensive physiological influence in the central nervous system (CNS) and various behavioral and biological functions, including immune regulation through 5-HT receptors (5-HTRs) expressed by immune cells. A variety of serotonin-modulating drugs have been developed to treat neurological disorders. Phenelzine, a drug indicated for the management of treatment-resistant depression, is a potent, non-selective inhibitor of monoamine oxidase (MAO), the enzyme that metabolizes serotonin to 5-hydroxyindole acetic acid (5-HIAA). Given the emerging evidence of a bidirectional link between depression and inflammation, as well as the potential therapeutic applications of serotonin-modulating drugs in autoimmune diseases and cancer, our study investigated the pro-inflammatory and anti-inflammatory factors influenced by serotonin and phenelzine. Methodology We conducted experiments on RAW264.7 macrophages, exposing them to various combinations and concentrations of serotonin, 5-HIAA, and phenelzine. We assessed the relative gene expression of monoamine oxidase-A (MAO-A), CYP1B1, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) using real-time PCR and measured the production of IL-6, TNF-α, and IL-10 cytokines using enzyme-linked immunosorbent assays (ELISA). Results Our findings revealed that phenelzine can downregulate genes associated with the production of reactive oxygen and nitrogen species, reduce aryl hydrocarbon receptor (AHR)-related gene expression induced by serotonin, and enhance the production of inflammatory cytokines. These effects were significantly influenced by the concentration of available serotonin. Conclusions Our study demonstrates that various mechanisms, including AHR activation, modulation of reactive oxygen and nitrogen species production, and others, in addition to the increased availability of serotonin due to phenelzine treatment, can significantly influence the inflammatory state.
背景
血清素（5-羟色胺，5-HT）是一种神经递质，在中枢神经系统（CNS）中具有广泛的生理影响，并参与各种行为和生物学功能，包括通过免疫细胞表达的5-羟色胺受体（5-HTRs）进行免疫调节。已开发出多种血清素调节药物来治疗神经系统疾病。苯乙肼是一种用于治疗难治性抑郁症的药物，它是一种强效、非选择性的单胺氧化酶（MAO）抑制剂，MAO可将血清素代谢为5-羟吲哚乙酸（5-HIAA）。鉴于抑郁症与炎症之间双向联系的新证据，以及血清素调节药物在自身免疫性疾病和癌症中的潜在治疗应用，我们的研究调查了血清素和苯乙肼对促炎和抗炎因子的影响。
方法
我们对RAW264.7巨噬细胞进行实验，将它们暴露于血清素、5-HIAA和苯乙肼的各种组合及浓度下。我们使用实时聚合酶链反应（PCR）评估单胺氧化酶-A（MAO-A）、细胞色素P450 1B1（CYP1B1）、环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的相对基因表达，并使用酶联免疫吸附测定（ELISA）测量白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素-10（IL-10）细胞因子的产生。
结果
我们的研究结果表明，苯乙肼可下调与活性氧和氮物种产生相关的基因，降低血清素诱导的芳烃受体（AHR）相关基因表达，并增强炎性细胞因子的产生。这些效应受到可利用血清素浓度的显著影响。
结论
我们的研究表明，除了苯乙肼治疗导致血清素可用性增加外，包括AHR激活、活性氧和氮物种产生的调节等多种机制，均可显著影响炎症状态。
