D'Argenio Giuseppe, Valenti Marta, Scaglione Giuseppe, Cosenza Vittorio, Sorrentini Italo, Di Marzo Vincenzo
Gastroenterologia, Università di Napoli Federico II, Naples, Italy.
FASEB J. 2006 Mar;20(3):568-70. doi: 10.1096/fj.05-4943fje. Epub 2006 Jan 10.
Direct stimulation of cannabinoid CB1 receptors exerts a protective function in animal models of inflammatory bowel diseases (IBDs). However, it is not known whether endocannabinoids are up-regulated during IBDs in animals or humans, nor whether pharmacological elevation of endocannabinoid levels can be exploited therapeutically in these disorders. In this study we addressed these questions. Colon inflammation was induced in mice and rats with 2,4-dinitrobenzene- and 2,4,6-trinitrobenzene sulfonic acids (DNBS and TNBS), respectively. DNBS-treated mice were treated chronically (for 3 or 7 days) with inhibitors of anandamide enzymatic hydrolysis (N-arachidonoyl-serotonin, AA-5-HT) or reuptake (VDM11), 10 or 5 mg/kg, s.c., or with 5-amino-salicilic acid (5-ASA, 1.4 mg/kg, i.r.). Endocannabinoids (anandamide and 2-arachidonoylglycerol, 2-AG) were quantified in mouse colon, or in rat colon mucosa and submucosa, and in bioptic samples from the colon of patients with untreated ulcerative colitis, by liquid chromatography-mass spectrometry. A strong elevation of anandamide, but not 2-AG, levels was found in the colon of DNBS-treated mice, in the colon submucosa of TNBS-treated rats, and in the biopsies of patients with ulcerative colitis. VDM-11 significantly elevated anandamide levels in the colon of DNBS-treated mice and concomitantly abolished inflammation, whereas AA-5-HT did not affect endocannabinoid levels and was significantly less efficacious at attenuating colitis. 5-ASA also increased anandamide levels and abolished colitis. Thus, anandamide is elevated in the inflamed colon of patients with ulcerative colitis, as well as in animal models of IBDs, to control inflammation, and elevation of its levels with inhibitors of its cellular reuptake might be used in the treatment of IBDs.
在炎症性肠病（IBD）动物模型中，直接刺激大麻素CB1受体可发挥保护作用。然而，尚不清楚内源性大麻素在动物或人类IBD期间是否上调，也不清楚内源性大麻素水平的药理学升高是否可用于这些疾病的治疗。在本研究中，我们解决了这些问题。分别用2,4 -二硝基苯磺酸和2,4,6 -三硝基苯磺酸（DNBS和TNBS）在小鼠和大鼠中诱导结肠炎症。用10或5 mg/kg皮下注射的花生四烯乙醇胺酶促水解抑制剂（N -花生四烯酰 - 5 -羟色胺，AA - 5 - HT）或再摄取抑制剂（VDM11），或1.4 mg/kg腹腔注射的5 -氨基水杨酸（5 - ASA）对DNBS处理的小鼠进行长期（3或7天）治疗。通过液相色谱 - 质谱法对小鼠结肠、大鼠结肠黏膜和黏膜下层以及未经治疗的溃疡性结肠炎患者结肠活检样本中的内源性大麻素（花生四烯乙醇胺和2 -花生四烯酰甘油，2 - AG）进行定量。在DNBS处理的小鼠结肠、TNBS处理的大鼠结肠黏膜下层以及溃疡性结肠炎患者的活检样本中，发现花生四烯乙醇胺水平显著升高，而2 - AG水平未升高。VDM - 11显著提高了DNBS处理小鼠结肠中的花生四烯乙醇胺水平，并同时消除了炎症，而AA - 5 - HT不影响内源性大麻素水平，在减轻结肠炎方面效果显著较差。5 - ASA也提高了花生四烯乙醇胺水平并消除了结肠炎。因此，花生四烯乙醇胺在溃疡性结肠炎患者的炎症结肠以及IBD动物模型中升高，以控制炎症，并且用其细胞再摄取抑制剂提高其水平可能用于IBD的治疗。
