Pekiner Bilgehan, Ulusu Nuray N, Das-Evcimen Net, Sahilli Meral, Aktan Fugen, Stefek Milan, Stolc Svorad, Karasu Cimen
Department of Biochemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
Biochim Biophys Acta. 2002 Oct 9;1588(1):71-8. doi: 10.1016/s0925-4439(02)00141-2.
Hyperglycemia leads to excess production of reactive oxygen species (ROS), lipid peroxidation and protein glycation that may impair cellular calcium homeostasis and results in calcium sequestration and dysfunction in diabetic tissues. Stobadine (ST) is a pyridoindole antioxidant has been postulated as a new cardio- and neuroprotectant. This study was undertaken to test the hypothesis that the treatment with ST inhibits calcium accumulation, reduces lipid peroxidation and protein glycation and can change Ca2+,Mg2+-ATPase activity in diabetic animals. The effects of vitamin E treatment were also evaluated and compared with the effects of combined treatment with ST. Diabetes was induced by streptozotocin (STZ, 55 mg/kg i.p.). Some of diabetic rats and their age-matched controls were treated orally with a low dose of ST (24.7 mg/kg/day), vitamin E (400-500 IU/kg/day) or ST plus vitamin E for 10 weeks. ST and vitamin E separately produced, in a similar degree, reduction in diabetes-induced hyperglycemia. Each antioxidant alone significantly lowered the levels of plasma lipid peroxidation, cardiac and hepatic protein glycation in diabetic rats but vitamin E treatment was found to be more effective than ST treatment alone. Diabetes-induced increase in plasma triacylglycerol levels was not significantly altered by vitamin E treatment but markedly reduced by ST alone. The treatment with each antioxidant completely prevented calcium accumulation in diabetic heart and liver. Microsomal Ca2+,Mg2+-ATPase activity significantly decreased in both tissues of untreated diabetic rats. ST alone significantly increased microsomal Ca2+,Mg2+-ATPase activity in the heart of normal rats. However, neither treatment with ST nor vitamin E alone, nor their combination did change cardiac Ca2+,Mg2+-ATPase activity in diabetic heart. In normal rats, neither antioxidant had a significant effect on hepatic Ca2+,Mg2+-ATPase activity. Hepatic Ca2+,Mg2+-ATPase activity of diabetic rats was not changed by single treatment with ST, while vitamin E alone completely prevented diabetes-induced inhibition in microsomal Ca2+,Mg2+-ATPase activity in liver. Combined treatment with ST and vitamin E provided more benefits in the reduction of hyperglycemia and lipid peroxidation in diabetic animals. This study describes potential mechanisms on cellular effects of ST in the presence of diabetes-induced hyperglycemia that may delay or inhibit the development of diabetic complications. The use of ST together with vitamin E can better control hyperglycemia-induced oxidative stress.
高血糖会导致活性氧（ROS）过量产生、脂质过氧化和蛋白质糖基化，这可能会损害细胞钙稳态，并导致糖尿病组织中的钙螯合和功能障碍。司他定（ST）是一种吡啶并吲哚抗氧化剂，被认为是一种新型的心脏和神经保护剂。本研究旨在验证以下假设：用ST治疗可抑制糖尿病动物的钙积累，减少脂质过氧化和蛋白质糖基化，并能改变Ca2+、Mg2+-ATP酶活性。还评估了维生素E治疗的效果，并与ST联合治疗的效果进行了比较。通过腹腔注射链脲佐菌素（STZ，55 mg/kg）诱导糖尿病。一些糖尿病大鼠及其年龄匹配的对照组口服低剂量的ST（24.7 mg/kg/天）、维生素E（400 - 500 IU/kg/天）或ST加维生素E，持续10周。ST和维生素E分别在相似程度上降低了糖尿病诱导的高血糖。每种抗氧化剂单独使用均能显著降低糖尿病大鼠血浆脂质过氧化、心脏和肝脏蛋白质糖基化水平，但发现维生素E治疗比单独使用ST治疗更有效。维生素E治疗并未显著改变糖尿病诱导的血浆三酰甘油水平升高，但单独使用ST可使其显著降低。每种抗氧化剂治疗均能完全防止糖尿病心脏和肝脏中的钙积累。未治疗的糖尿病大鼠的两个组织中微粒体Ca2+、Mg2+-ATP酶活性均显著降低。单独使用ST可显著提高正常大鼠心脏中的微粒体Ca2+、Mg2+-ATP酶活性。然而，单独使用ST或维生素E治疗，以及它们的联合使用均未改变糖尿病心脏中的心脏Ca2+、Mg2+-ATP酶活性。在正常大鼠中，两种抗氧化剂对肝脏Ca2+、Mg2+-ATP酶活性均无显著影响。单独使用ST治疗未改变糖尿病大鼠的肝脏Ca2+、Mg2+-ATP酶活性，而单独使用维生素E可完全防止糖尿病诱导的肝脏微粒体Ca2+、Mg2+-ATP酶活性抑制。ST和维生素E联合治疗在降低糖尿病动物的高血糖和脂质过氧化方面提供了更多益处。本研究描述了在糖尿病诱导的高血糖存在下ST对细胞作用的潜在机制，这可能会延迟或抑制糖尿病并发症的发展。将ST与维生素E联合使用可以更好地控制高血糖诱导的氧化应激。
