Astroglial pentose phosphate pathway rates in response to high-glucose environments.
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.
Department of Neurology, Keio University School of Medicine, Shinjukuku, Tokyo, Japan. takashin@tka.att.ne.jp
Shinichi
S
Takahashi
Yoshikane
Y
Izawa
Norihiro
N
Suzuki
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002127:Calcium Isotopes / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003847:Deoxyglucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D021382:Protein Sorting Signals; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013997:Time Factors; D000091342:Endoplasmic Reticulum Chaperone BiP
D002127:Calcium Isotopes; D003847:Deoxyglucose; D005947:Glucose; D005978:Glutathione; D017127:Glycation End Products, Advanced; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D008239:Lysine; D051267:NF-E2-Related Factor 2; D009842:Oligopeptides; D021382:Protein Sorting Signals; D017382:Reactive Oxygen Species; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C073762:lysyl-aspartyl-glutamyl-leucine