Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation
Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation
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DOI：
10.1096/fj.05-4943fje
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发表时间：
2006-01-01
期刊：
影响因子：
4.8
通讯作者：
Di Marzo, V
中科院分区：
文献类型：
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作者：
D'Argenio, G;Valenti, M;Di Marzo, V
直接刺激大麻素CB1受体在炎症性肠病(IBD)动物模型中发挥保护作用。然而，目前尚不清楚在动物或人类IBD期间内源性大麻素是否上调，也不清楚药物上调内源性大麻素水平是否可以用于这些疾病的治疗。在这项研究中，我们解决了这些问题。用2，4-二硝基苯磺酸(DNBS)和2，4，6-三硝基苯磺酸(TNBS)分别诱导小鼠和大鼠结肠炎症。给DNBS处理的小鼠长期(连续3或7天)给予5-羟色胺酶解抑制剂(AA-5-HT)或再摄取抑制剂(VDM11)，10或5 mg/kg，sc，或5-氨基水杨酸(5-ASA，1.4 mg/kg，i.r)。用液-质联用法定量测定了小鼠结肠、大鼠结肠粘膜和粘膜下层，以及未经治疗的溃疡性结肠炎患者结肠活检标本中的内源性大麻素(anandide和2-花生四烯酸甘油，2-AG)。在DNBS治疗的小鼠的结肠、TNBS治疗的大鼠的结肠粘膜下层和溃疡性结肠炎患者的活检组织中，发现Anandamide水平显著升高，但不是2-AG水平。VDM-11显著增加了DNBS处理的小鼠结肠中的ANANDAME水平，同时也消除了炎症，而AA-5-HT不影响内源性大麻素的水平，在减轻结肠炎方面的效果明显较差。5-ASA还提高了ANANDA水平，消除了结肠炎。因此，在溃疡性结肠炎患者的炎症结肠中，以及在IBD的动物模型中，ANANDAME水平升高，以控制炎症，并且通过抑制其细胞重摄取来提高其水平，可能用于IBD的治疗。
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.