Insulin reduces cerebral ischemia/reperfusion injury in the hippocampus of diabetic rats: a role for glycogen synthase kinase-3beta.
Insulin reduces cerebral ischemia/reperfusion injury in the hippocampus of diabetic rats: a role for glycogen synthase kinase-3beta.
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DOI：
10.2337/db08-0691
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发表时间：
2009-01
期刊：
影响因子：
7.7
通讯作者：
Fantozzi, Roberto
中科院分区：
文献类型：
--
作者：
Collino, Massimo;Aragno, Manuela;Castiglia, Sara;Tomasinelli, Chiara;Thiemermann, Christoph;Boccuzzi, Giuseppe;Fantozzi, Roberto
有证据表明，胰岛素可以减少缺血/再灌注（I/R）引起的脑损伤。然而，胰岛素保护作用的分子机制仍然未知。胰岛素是一种众所周知的糖原合成酶激酶-3 β（GSK-3β）抑制剂。在此，我们研究了GSK-3β抑制在胰岛素缺乏性糖尿病大鼠模型中I/R诱导的脑损伤中的作用。研究设计和方法：将链脲佐菌素诱导的糖尿病大鼠颈总动脉闭塞30分钟，然后再灌注1或24小时。胰岛素（2-12 IU/kg i. v.）或选择性GSK-3β抑制剂TDZD-8（0.2-3 mg/kg i. v.）在再灌注期间进行。结果-胰岛素或TDZD-8显着减少梗死体积和S100 B蛋白（脑损伤标志物）的水平。两种药物均诱导Ser 9残基的磷酸化，从而使大鼠海马中的GSK-3β失活。胰岛素，但不是TDZD-8，降低血糖。药物治疗的动物的大脑显示减少氧化应激在1小时的再灌注所示的减少产生的活性氧和脂质过氧化反应。I/R诱导的核因子-κB活化被两种药物治疗减弱。在再灌注24 h时，TDZD-8和胰岛素显著降低了肿瘤坏死因子-α的血浆水平;中性粒细胞浸润（以髓过氧化物酶活性和细胞间粘附分子-1表达测量）;以及环氧合酶-2和诱导型NO-合酶表达。结论：胰岛素或TDZD-8的急性给药减少了糖尿病大鼠的脑I/R损伤。我们认为，对GSK-3β活性的抑制作用有助于胰岛素的保护作用，而不依赖于对血糖的任何影响。
OBJECTIVE—There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3β (GSK-3β). Here, we investigate the role of GSK-3β inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes. RESEARCH DESIGN AND METHODS—Rats with streptozotocin-induced diabetes were subjected to 30-min occlusion of common carotid arteries followed by 1 or 24 h of reperfusion. Insulin (2–12 IU/kg i.v.) or the selective GSK-3β inhibitor TDZD-8 (0.2–3 mg/kg i.v.) was administered during reperfusion. RESULTS—Insulin or TDZD-8 dramatically reduced infarct volume and levels of S100B protein, a marker of cerebral injury. Both drugs induced phosphorylation of the Ser9 residue, thereby inactivating GSK-3β in the rat hippocampus. Insulin, but not TDZD-8, lowered blood glucose. The hippocampi of the drug-treated animals displayed reduced oxidative stress at 1 h of reperfusion as shown by the decreased generation of reactive oxygen species and lipid peroxidation. I/R-induced activation of nuclear factor-κB was attenuated by both drug treatments. At 24 h of reperfusion, TDZD-8 and insulin significantly reduced plasma levels of tumor necrosis factor-α; neutrophil infiltration, measured as myeloperoxidase activity and intercellular-adhesion-molecule-1 expression; and cyclooxygenase-2 and inducible-NO-synthase expression. CONCLUSIONS—Acute administration of insulin or TDZD-8 reduced cerebral I/R injury in diabetic rats. We propose that the inhibitory effect on the activity of GSK-3β contributes to the protective effect of insulin independently of any effects on blood glucose.
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