Bertoni Simona, Arcaro Valentina, Vivo Valentina, Rapalli Alberto, Tognolini Massimiliano, Cantoni Anna Maria, Saccani Francesca, Flammini Lisa, Domenichini Giuseppe, Ballabeni Vigilio, Barocelli Elisabetta
Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.
Pharmacol Res. 2014 Mar;81:17-25. doi: 10.1016/j.phrs.2014.02.002. Epub 2014 Feb 16.
Intestinal ischemia and reperfusion (I/R) is a potentially life-threatening disease, ensuing from various clinical conditions. Experimentally, either protective or detrimental roles have been attributed to 5-HT in the functional and morphological injury caused by mesenteric I/R. Recently, we proved the involvement of 5-HT2A receptors in the intestinal dysmotility and leukocyte recruitment induced by 45min occlusion of the superior mesenteric artery (SMA) followed by 24h reperfusion in mice. Starting from these premises, the aim of our present work was to investigate the role played by endogenous 5-HT in the same experimental model where 45min SMA clamping was followed by 5h reflow. To this end, we first observed that ischemic preconditioning before I/R injury (IPC+I/R) reverted the increase in 5-HT tissue content and in inflammatory parameters induced by I/R in mice. Second, the effects produced by intravenous administration of 5-HT1A ligands (partial agonist buspirone 10mgkg(-1), antagonist WAY100135 0.5-5mgkg(-1)), 5-HT2A antagonist sarpogrelate (10mgkg(-1)), 5-HT3 antagonist alosetron (0.1mgkg(-1)), 5-HT4 antagonist GR125487 (5mgkg(-1)) and 5-HT re-uptake inhibitor fluoxetine (10mgkg(-1)) on I/R-induced inflammatory response were investigated in I/R mice and compared to those obtained in sham-operated animals (S). Our results confirmed the significant role played by 5-HT2A receptors not only in the late but also in the early I/R-induced microcirculatory dysfunction and showed that blockade of 5-HT1A receptors protected against the intestinal leukocyte recruitment, plasma extravasation and reactive oxygen species formation triggered by SMA occlusion and reflow. The ability of α7 nicotinic receptor (α7nAchR) antagonist methyllycaconitine (5mgkg(-1)) to counteract the beneficial action provided by buspirone on I/R-induced neutrophil infiltration suggests that the anti-inflammatory effect produced by 5-HT1A receptor antagonism could be partly ascribed to the indirect activation of α7nAch receptors.
肠缺血再灌注（I/R）是一种由多种临床情况引发的、可能危及生命的疾病。在实验中，5-羟色胺（5-HT）在肠系膜I/R所致的功能和形态损伤中既发挥保护作用，也有有害作用。最近，我们证实了5-HT2A受体参与了小鼠肠系膜上动脉（SMA）闭塞45分钟后再灌注24小时所诱导的肠道运动障碍和白细胞募集。基于这些前提，我们当前工作的目的是在45分钟SMA夹闭后再灌注5小时的同一实验模型中，研究内源性5-HT所起的作用。为此，我们首先观察到，I/R损伤前的缺血预处理（IPC+I/R）可逆转I/R诱导的小鼠5-HT组织含量增加和炎症参数升高。其次，在I/R小鼠中研究了静脉注射5-HT1A配体（部分激动剂丁螺环酮10mgkg(-1)、拮抗剂WAY100135 0.5 - 5mgkg(-1)）、5-HT2A拮抗剂沙格雷酯（10mgkg(-1)）、5-HT3拮抗剂阿洛司琼（0.1mgkg(-1)）、5-HT4拮抗剂GR125487（5mgkg(-1)）和5-HT再摄取抑制剂氟西汀（10mgkg(-1)）对I/R诱导的炎症反应的影响，并与假手术动物（S）的结果进行比较。我们的结果证实了5-HT2A受体不仅在I/R诱导的晚期，而且在早期微循环功能障碍中都发挥着重要作用，并且表明阻断5-HT1A受体可防止SMA闭塞和再灌注引发的肠道白细胞募集、血浆外渗和活性氧形成。α7烟碱受体（α7nAchR）拮抗剂甲基lycaconitine（5mgkg(-1)）抵消丁螺环酮对I/R诱导的中性粒细胞浸润的有益作用的能力表明，5-HT1A受体拮抗产生的抗炎作用可能部分归因于α7nAch受体的间接激活。
