Cuzzocrea Salvatore, Malleo Giuseppe, Genovese Tiziana, Mazzon Emanuela, Esposito Emanuela, Muià Carmelo, Abdelrahman Maha, Di Paola Rosanna, Thiemermann Cristoph
Department of Clinical, Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy. salvator@.unime.it
Crit Care Med. 2007 Dec;35(12):2811-21. doi: 10.1097/01.ccm.0000295303.62996.9f.
Glycogen synthase kinase (GSK)-3 is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and signal transduction pathways. It also plays an important role in the pathophysiology of a number of diseases characterized by an enhanced or unregulated inflammatory response. Here we investigate the effects of GSK-3beta inhibition on the development of experimental acute pancreatitis induced by cerulein in mice.
Prospective, randomized study.
University-based research laboratory.
One-hundred and sixty anesthetized male CD mice.
Pancreatitis was induced by intraperitoneal injection of cerulein (hourly x5, 50 microg/kg). In the treatment group, the potent and selective GSK-3beta inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered 1 hr and 6 hrs after the first injection of cerulein (10 mg/kg, intraperitoneally). Sham groups were treated with vehicle (0.1 mL of 0.9% NaCl, intraperitoneally) and TDZD-8. In another set of experiments, mice were monitored for 24 days to determine their mortality rate.
The injection of cerulein resulted in acute necrotizing pancreatitis. TDZD-8 significantly reduced the degree of pancreas injury, amylase, and lipase serum levels (p < .01); nuclear factor-kappaB activation (p < .01); the production of tumor necrosis factor-alpha and interleukin-1beta (p < .01); the expression of adhesion molecules and neutrophil accumulation (p < .01); the formation of oxygen and nitrogen-derived radicals (p < .01); the degree of lipid peroxidation (p < .01); the expression of transforming growth factor-beta and vascular endothelial growth factor (p < .01); and-ultimately-the mortality rate (p < .01).
Inhibition of GSK-3beta reduces the degree of cerulein-induced acute pancreatitis and the associated mortality rate in mice. Blocking protein kinase activity may be a novel approach to treatment of this inflammatory condition.
糖原合酶激酶（GSK）-3是一种普遍存在的丝氨酸-苏氨酸蛋白激酶，参与多种细胞过程和信号转导途径。它在许多以炎症反应增强或失控为特征的疾病的病理生理学中也起着重要作用。在此，我们研究GSK-3β抑制对小鼠中由雨蛙肽诱导的实验性急性胰腺炎发展的影响。
前瞻性随机研究。
大学基础研究实验室。
160只麻醉的雄性CD小鼠。
通过腹腔注射雨蛙肽（每小时一次，共5次，50微克/千克）诱导胰腺炎。在治疗组中，在首次注射雨蛙肽（10毫克/千克，腹腔注射）后1小时和6小时给予强效选择性GSK-3β抑制剂4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮（TDZD-8）。假手术组用溶媒（0.1毫升0.9%氯化钠，腹腔注射）和TDZD-8治疗。在另一组实验中，对小鼠进行24天监测以确定其死亡率。
注射雨蛙肽导致急性坏死性胰腺炎。TDZD-8显著降低胰腺损伤程度、淀粉酶和脂肪酶血清水平（p < 0.01）；核因子-κB激活（p < 0.01）；肿瘤坏死因子-α和白细胞介素-1β的产生（p < 0.01）；黏附分子表达和中性粒细胞聚集（p < 0.01）；氧自由基和氮自由基的形成（p < 0.01）；脂质过氧化程度（p < 0.01）；转化生长因子-β和血管内皮生长因子的表达（p < 0.01）；最终降低死亡率（p < 0.01）。
抑制GSK-3β可降低雨蛙肽诱导的小鼠急性胰腺炎程度及相关死亡率。阻断蛋白激酶活性可能是治疗这种炎症性疾病的一种新方法。
