Effects of the seleno-organic substance Ebselen in two different models of acute pancreatitis.
Effects of the seleno-organic substance Ebselen in two different models of acute pancreatitis.
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有机硒物质 Ebselen 对两种不同急性胰腺炎模型的影响。
DOI：
10.1097/00006676-199105000-00005
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发表时间：
1991
期刊：
影响因子：
2.9
通讯作者：
Grendell,JH
中科院分区：
文献类型：
--
作者：
Niederau,C;Ude,K;Niederau,M;Lüthen,R;Strohmeyer,G;Ferrell,LD;Grendell,JH
本研究评价了硒有机物Ebselen [2-苯基-1，2-苯并异硒唑-3（2 H）-酮]对急性出血性和急性水肿性胰腺炎两种模型的作用。已知依布硒啉催化谷胱甘肽过氧化物酶样反应并抑制脂质过氧化。通过给小鼠喂食胆碱缺乏、乙硫氨酸补充（CDE）饲料66 h诱导出血性胰腺炎。水肿性胰腺炎诱导7小时皮下注射50 [mu]-g/kg的雨蛙肽的小鼠。依布硒啉从CDE饲料开始时以100 mg/kg皮下注射给药，间隔6小时，或与CDE饲料混合，以产生100 mg/kg的依布硒啉日剂量。在进一步的实验中，在CDE饮食开始后的不同时间间隔给予依布硒啉，以6小时间隔皮下注射100 mg/kg。在雨蛙肽模型中，在每次注射雨蛙肽之前5分钟给予依布硒啉，剂量为10-500 mg/kg。口服或皮下给予依布硒啉的预防性给药显著提高了存活率，从盐水注射CDE喂养小鼠对照组的38.5%分别提高到61.9%和65.0%。依布硒啉还降低了饮食模型中血清淀粉酶和胰腺重量的增加。治疗性给予依布硒林仅在开始CDE饮食后20小时开始注射时显著增加存活率（64%），但在40小时后开始注射时则不显著（44%）。同样，仅在20 h后开始注射时，Ebselen显著降低了CDE饮食引起的血清淀粉酶和胰腺重量增加，但在40 h后开始注射时则没有。在蛙皮素诱导的胰腺炎中，Ebselen轻微改善胰腺重量的增加，这反映了水肿（p< 0.05），但没有减少血清淀粉酶的增加（p> 0.2）。由于有机硒物质降低了现有两种模型中的胰腺重量，因此急性胰腺炎的水肿可能是由于氧源性自由基的产生造成的。虽然依布硒伦仅轻微降低CDE饮食诱导的坏死程度，但即使在胰腺炎发作后给药，也能显著降低该模型的死亡率。因此，硒有机化合物不仅可以通过作用于原发性胰腺病变，而且还可以作用于胰腺外并发症，这些并发症导致出血性胰腺炎动物模型以及人类疾病中的死亡率。
This study evaluated the effects of the seleno-organic substance Ebselen [2-phenyl-l, 2-benzisoselenazol-3 (2H)-one] in two models of acute hemorrhagic and acute edematous pancreatitis. Ebselen is known to catalyze glutathione peroxidase-like reactions and to inhibit lipid peroxidation. Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice for 66 h. Edematous pancreatitis was induced by 7-h subcutaneous injections of 50 [mu]-g/kg of cerulein in mice. Ebselen was given from the beginning of the CDE diet either as a subcutaneous injection of 100 mg/kg at 6-h intervals or was mixed in with the CDE diet to yield a daily dose of 100 mg/kg of Ebselen. In further experiments, Ebselen was given at various time intervals after the beginning of the CDE diet as subcutaneous injections of 100 mg/kg at 6-h intervals. In the cerulein model, Ebselen was given 5 min prior to each cerulein injection at doses from 10-500 mg/kg. Prophylactic administration of Ebselen given orally or subcutaneously significantly improved survival from 38.5% in the control group of saline-injected CDE-fed mice to 61.9 and 65.0%, respectively. Ebselen also reduced increases in serum amylase and pancreatic weight in the diet model. Therapeutic administration of Ebselen significantly increased survival only when injections were started 20 h after the beginning of the CDE diet (64%), but not when started after 40 h (44%). Similarly, increases in serum amylase and pancreatic weight due to the CDE diet were significantly reduced by Ebselen only when injections were started after 20 h but not when started after 40 h. In cerulein-induced pancreatitis, Ebselen slightly ameliorated the increase in pancreatic weight, which reflects edema (p< 0.05), but did not reduce the increase in serum amylase (p> 0.2). Since the selenoorganic substance reduced pancreatic weight in both present models, edema in acute pancreatitis might result from generation of oxygen-derived free radicals. Although Ebselen only slightly reduced the degree of necrosis induced by the CDE diet, it markedly reduced mortality in this model even when administered after the onset of pancreatitis. Thus, the selenoorganic compound may exert its beneficial effects on survival not only by acting on the primary pancreatic lesion, but it may in addition act on extrapancreatic complications that contribute to mortality in this animal model of hemorrhagic pancreatitis as well as in the human disease.
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