Yu Bangning, Becnel Jaime, Zerfaoui Mourad, Rohatgi Rasika, Boulares A Hamid, Nichols Charles D
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA, USA.
J Pharmacol Exp Ther. 2008 Nov;327(2):316-23. doi: 10.1124/jpet.108.143461. Epub 2008 Aug 15.
The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)(2A) receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT(2A) receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-alpha-mediated inflammation. 5-HT(2A) receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor kappaB, with IC(50) values of only 10 to 20 pM. It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-alpha. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT(2A) receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-alpha-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing.
G蛋白偶联血清素5-羟色胺（5-HT）（2A）受体主要因其在大脑神经传递中的作用而被认可，它在大脑中介导多种功能，包括认知的某些方面。然而，该受体在周围组织中也有显著表达，其重要性在很大程度上尚不清楚。我们现已发现，在原代主动脉平滑肌细胞中激活5-HT（2A）受体可对肿瘤坏死因子（TNF）-α介导的炎症产生前所未知且极其强效的抑制作用。用激动剂（R）-1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷[（R）-DOI]刺激5-HT（2A）受体可迅速抑制多种TNF-α介导的促炎标志物，包括细胞间黏附分子1（ICAM-1）、血管黏附分子1（VCAM-1）以及白细胞介素（IL）-6基因表达、一氧化氮合酶活性和核因子κB的核转位，半数抑制浓度（IC50）值仅为10至20皮摩尔。值得注意的是，在用TNF-α处理数小时后，（R）-DOI也能抑制促炎标志物。除了少数天然毒素外，目前没有任何药物或小分子疗法对任何生理效应具有类似的效力。TNF-α介导的炎症途径与多种疾病密切相关，包括动脉粥样硬化、类风湿性关节炎、银屑病、II型糖尿病、抑郁症、精神分裂症和阿尔茨海默病。我们的结果表明，激活5-HT（2A）受体代表了一种用于治疗涉及TNF-α介导炎症的疾病的新型且极其有效的潜在治疗途径。请注意，由于（R）-DOI在给予TNF-α数小时后仍能显著抑制TNF-α的作用，潜在疗法不仅可以旨在预防炎症，还可以治疗已经发生或正在进行的炎症损伤。
