Department of Neurology, Keio University School of Medicine, Shinjukuku, Tokyo, Japan.
ASN Neuro. 2012 Mar 22;4(2):e00078. doi: 10.1042/AN20120002.
ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of (14)CO(2) production from [1-(14)C]glucose and [6-(14)C]glucose. ROS production, mainly H(2)O(2), and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke.
活性氧（ROS）在糖尿病、中风和神经退行性疾病的病理生理学中起着至关重要的作用。与糖尿病相关的高血糖会增强 ROS 的产生，并导致血管内皮细胞发生氧化应激，但急性或慢性高葡萄糖环境对脑实质细胞的不良影响仍不清楚。PPP（戊糖磷酸途径）和 GSH 参与了大脑中针对 ROS 的主要防御机制，我们探讨了星形胶质细胞 PPP 在应对急性和慢性高葡萄糖环境中的作用和调节。通过测定[1-（14）C]葡萄糖和[6-（14）C]葡萄糖产生（14）CO2 的速率来测量培养神经元和星形胶质细胞中的 PPP 活性。还评估了 ROS 产生（主要是 H2O2）和 GSH。培养基中葡萄糖浓度的急性升高增加了星形胶质细胞中的 PPP 活性和 GSH 水平，减少了 ROS 的产生。慢性高葡萄糖环境也诱导了 PPP 的激活。免疫组织化学分析显示，慢性高葡萄糖环境诱导 ER（内质网）应激（可能是通过增加己糖胺生物合成途径通量）。还观察到核因子-红细胞 2 p45 亚基相关因子 2（Nrf2）的核易位，Nrf2 通过增强转录来调节 G6PDH（甘油醛-3-磷酸脱氢酶），同时还观察到免疫球蛋白重链结合蛋白（BiP）的表达。急性和慢性高葡萄糖环境激活了星形胶质细胞中的 PPP，防止了 ROS 的升高。因此，血糖水平的快速下降似乎会增强 ROS 的毒性，当给予糖尿病患者的胰岛素水平未得到适当校准且血浆葡萄糖水平未得到充分维持时，可能会导致神经损伤。这些发现也可能解释了在中风的急性期严格血糖控制没有临床获益的证据缺乏的原因。
