Collino Massimo, Thiemermann Christoph, Mastrocola Raffaella, Gallicchio Margherita, Benetti Elisa, Miglio Gianluca, Castiglia Sara, Danni Oliviero, Murch Oliver, Dianzani Chiara, Aragno Manuela, Fantozzi Roberto
Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy.
Shock. 2008 Sep;30(3):299-307. doi: 10.1097/SHK.0b013e318164e762.
The serine/threonine glycogen synthase kinase 3beta (GSK-3beta) is abundant in the central nervous system, particularly in the hippocampus, and plays a pivotal role in the pathophysiology of a number of diseases, including neurodegeneration. This study was designed to investigate the effects of GSK-3beta inhibition against I/R injury in the rat hippocampus. Transient cerebral ischemia (30 min) followed by 1 h of reperfusion significantly increased generation of reactive oxygen species and modulated superoxide dismutase activity; 24 h of reperfusion evoked apoptosis (determined as mitochondrial cytochrome c release and Bcl-2 and caspase-9 expression), resulted in high plasma levels of TNF-alpha and increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and intercellular adhesion molecule-1. The selective GSK-3beta inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), was administered before and after ischemia or during reperfusion alone to assess its potential as prophylactic or therapeutic strategy. Prophylactic or therapeutic administration of TDZD-8 caused the phosphorylation (Ser(9)) and hence inactivation of GSK-3beta. Infarct volume and levels of S100B protein, a marker of cerebral injury, were reduced by TDZD-8. This was associated with a significant reduction in markers of oxidative stress, apoptosis, and the inflammatory response resulting from cerebral I/R. These beneficial effects were associated with a reduction of I/R-induced activation of the mitogen-activated protein kinases JNK1/2 and p38 and nuclear factor-kappaB. The present study demonstrates that TDZD-8 protects the brain against I/R injury by inhibiting GSK-3beta activity. Collectively, our data may contribute to focus the role of GSK-3beta in cerebral I/R.
丝氨酸/苏氨酸糖原合酶激酶3β（GSK - 3β）在中枢神经系统中含量丰富，尤其是在海马体中，并且在包括神经退行性变在内的多种疾病的病理生理学中发挥关键作用。本研究旨在探讨抑制GSK - 3β对大鼠海马体缺血/再灌注损伤的影响。短暂性脑缺血（30分钟）后再灌注1小时可显著增加活性氧的生成并调节超氧化物歧化酶活性；再灌注24小时可诱发细胞凋亡（通过线粒体细胞色素c释放以及Bcl - 2和半胱天冬酶 - 9表达来确定），导致血浆中肿瘤坏死因子 - α水平升高以及环氧化酶 - 2、诱导型一氧化氮合酶和细胞间黏附分子 - 1的表达增加。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）在缺血前后或仅在再灌注期间给药，以评估其作为预防或治疗策略的潜力。预防性或治疗性给予TDZD - 8会导致GSK - 3β磷酸化（Ser(9)）从而使其失活。TDZD - 8可减少梗死体积以及脑损伤标志物S100B蛋白的水平。这与氧化应激、细胞凋亡以及脑缺血/再灌注引起的炎症反应标志物的显著降低相关。这些有益作用与缺血/再灌注诱导的丝裂原活化蛋白激酶JNK1/2和p38以及核因子 - κB的激活减少有关。本研究表明，TDZD - 8通过抑制GSK - 3β活性保护大脑免受缺血/再灌注损伤。总体而言，我们的数据可能有助于明确GSK - 3β在脑缺血/再灌注中的作用。
