Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, 13145-784, 1416753955, Iran.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, 13145-784, Iran.
Pharmacol Rep. 2023 Jun;75(3):623-633. doi: 10.1007/s43440-023-00470-8. Epub 2023 Mar 15.
Mesenteric ischemia has remained without effective pharmacological management for many years. Sumatriptan, an abortive medication for migraine and cluster headaches, has potent anti-inflammatory properties and ameliorated organ ischemia in previous animal studies. Similarly, inhibition of the kynurenine pathway ameliorated renal and myocardial ischemia/reperfusion (I/R) in many preclinical studies. Herein, we assessed the effect of sumatriptan on experimental mesenteric I/R and investigated whether kynurenine pathway inhibition is a mechanism underlying its action.
Ischemia was induced by ligating the origin of the superior mesenteric artery (SMA) and its anastomosis with the inferior mesenteric artery (IMA) with bulldog clamps for 30 min. Ischemia was followed by 1 h of reperfusion. Sumatriptan (0.1, 0.3, and 1 mg/kg ip) was injected 5 min before the reperfusion phase, 1-methyltryptophan (1-MT) (100 mg/kg iv) was used to inhibit kynurenine production. At the end of the reperfusion phase, samples were collected from the jejunum of rats for H&E staining and molecular assessments.
Sumatriptan improved the integrity of intestinal mucosa after I/R, and 0.1 mg/kg was the most effective dose of sumatriptan in this study. Sumatriptan decreased the increased levels of TNF-α, kynurenine, and p-ERK but did not change the decreased levels of NO. Furthermore, sumatriptan significantly increased the decreased ratio of Bcl2/Bax. Similarly, 1-MT significantly decreased TNF-α and kynurenine and protected against mucosal damage.
This study demonstrated that sumatriptan has protective effects against mesenteric ischemia and the kynurenine inhibition is potentially involved in this process. Therefore, it can be assumed that sumatriptan has the potential to be repurposed as a treatment for acute mesenteric ischemia.
肠系膜缺血多年来一直没有有效的药物治疗方法。舒马曲坦是一种治疗偏头痛和丛集性头痛的特效药，具有很强的抗炎特性，并在前瞻性动物研究中改善了器官缺血。同样，在许多临床前研究中，抑制犬尿氨酸途径可改善肾和心肌缺血/再灌注（I/R）。在此，我们评估了舒马曲坦对实验性肠系膜 I/R 的影响，并研究了犬尿氨酸途径抑制是否是其作用的机制。
通过用斗牛犬夹结扎肠系膜上动脉（SMA）的起源及其与肠系膜下动脉（IMA）的吻合口来诱导缺血 30 分钟。然后进行 1 小时的再灌注。在再灌注阶段前 5 分钟，舒马曲坦（0.1、0.3 和 1mg/kg 腹腔注射）被注射，1-甲基色氨酸（1-MT）（100mg/kg 静脉注射）用于抑制犬尿氨酸的产生。在再灌注阶段结束时，从大鼠的空肠中采集样本进行 H&E 染色和分子评估。
舒马曲坦改善了 I/R 后的肠黏膜完整性，在本研究中，0.1mg/kg 的舒马曲坦是最有效的剂量。舒马曲坦降低了 TNF-α、犬尿氨酸和 p-ERK 的升高水平，但没有改变 NO 的降低水平。此外，舒马曲坦显著增加了 Bcl2/Bax 的降低比值。同样，1-MT 显著降低了 TNF-α 和犬尿氨酸，并保护了黏膜免受损伤。
本研究表明，舒马曲坦对肠系膜缺血具有保护作用，犬尿氨酸抑制可能参与了这一过程。因此，可以假设舒马曲坦有可能被重新用于治疗急性肠系膜缺血。
