1.3 Pentose Phosphate Pathway and NADPH Metabolism

Dringen, Ralf; Hoepken, Hans Herman; Minich, Tobias; Ruedig, Cornelia

doi:10.1007/978-0-387-30411-3_3

Cited by 42 publications

(36 citation statements)

References 182 publications

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“…The overall rate of brain glucose utilization is regulated in an integrated, complex manner by various regulatory metabolites at many steps, including at the initial step in glycolytic pathway, the phosphorylation of glucose to glucose 6-phosphate by hexokinase, as well as at many downstream sites, especially, phosphofructokinase (the major regulatory enzyme), pyruvate kinase, PDH (pyruvate dehydrogenase) and tricarboxylic acid cycle dehydrogenases. PPP fluxes are governed by NADP availability due to consumption of NADPH to regenerate GSH from GSSG as the cell manages oxidative stress (Dringen et al, 2007). Nitric oxide and peroxynitrite also strongly activate the PPP (García-Nogales et al, 2003), as do various neurotransmitters that are metabolized by monoamine oxidase and generate H 2 O 2 (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The PPP branches from the glycolytic pathway of glucose at glucose 6-phosphate, and the activity of the rate-limiting enzyme of the PPP, G6PDH (glyceraldehyde-6-phosphate dehydrogenase), is regulated by NADPH, peroxynitrite and other factors, as well as by transcriptional mechanisms (Dringen et al, 2007; Wamelink et al, 2008). The PPP is generally considered to be a minor pathway of glucose metabolism in resting brain, but it can be markedly up-regulated under various conditions (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…The PPP is generally considered to be a minor pathway of glucose metabolism in resting brain, but it can be markedly up-regulated under various conditions (e.g. Appel and Parrot, 1970) to generate NADPH, which in turn increases GSH to detoxify ROS in concert with glutathione peroxidase (Dringen et al, 2007). ‘Resting’ PPP rate and the magnitude of PPP increase during activation are known to be higher in astrocytes than in neurons, although they are not negligible in neurons (Ben-Yoseph et al, 1996a, 1996b; Delgado-Esteban et al, 2000; García-Nogales et al, 2003; Vaughn and Deshmukh, 2008; Herrero-Mendez et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Astroglial Pentose Phosphate Pathway Rates in Response to High-Glucose Environments

2012

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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 14CO2 production from [1-14C]glucose and [6-14C]glucose. ROS production, mainly H2O2, 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astroglial Pentose Phosphate Pathway Rates in Response to High-Glucose Environments

2012

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“…Through PPP glucose makes important contributions to anabolic processes in all organs of the body providing intermediates for cellular proliferation including NADPH, nucleotides for DNA replication [77], and intermediates for fatty acid synthesis [78,79] ( Figure 3 ). In animal experiments, estimates of the amount of glucose entering the PPP in the mature brain have been generally low [80]. …”

Section: Biosynthesismentioning

confidence: 99%

Brain aerobic glycolysis functions and Alzheimer’s disease

Vlassenko

Raichle

2014

Clin Transl Imaging

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Genetic, biochemical, pathological, and biomarker data demonstrate that Alzheimer’s disease (AD) pathology, including the initiation and progressive buildup of insoluble forms of beta-amyloid (Aβ), appears to begin ~ 10-15 years prior to the onset of cognitive decline associated with AD. Metabolic dysfunction, a prominent feature of the evolving brain pathology, is reflected in a decline of total glucose utilization. Despite decades of interest in declining glucose use in AD no detailed consideration had been given to the possibility that this decline is not just a decline in energy consumption but rather in glycolysis alone. Glycolysis is a multi-step process that prepares the glucose molecule for oxidative phosphorylation and the generation of energy. In the normal brain, glycolysis exceeds that required for the needs of oxidative phosphorylation. Because it is occurring in a setting with adequate oxygen available for oxidative phosphorylation it is often referred to as aerobic glycolysis (AG). AG is a biomarker of a group of metabolic functions broadly supporting biosynthesis and neuroprotection. The distribution of AG in normal young adults correlates spatially with Aβ deposition in AD patients and cognitively normal individuals with elevated Aβ. In transgenic mice extracellular fluid Aβ and lactate, a marker of AG, vary in parallel regionally and with changes in activity. Reducing neuronal activity locally in transgenic mice attenuates plaque formation suggesting that plaque formation is an activity dependent process associated with aerobic glycolysis.

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“…3.6) has two major roles: provision of NADPH that is utilized in biosynthetic reactions and oxidative defense, and generation of 5-carbon intermediates that are precursors for nucleic acids (Dringen et al, 2007). 3.6) has two major roles: provision of NADPH that is utilized in biosynthetic reactions and oxidative defense, and generation of 5-carbon intermediates that are precursors for nucleic acids (Dringen et al, 2007).…”

Section: Pentose Phosphate Shunt Pathway: Oxidative Defense and Biosymentioning

confidence: 99%

Energy Metabolism in the Brain

Dienel¹

2014

From Molecules to Networks

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1.3 Pentose Phosphate Pathway and NADPH Metabolism

Cited by 42 publications

References 182 publications

Astroglial Pentose Phosphate Pathway Rates in Response to High-Glucose Environments

Astroglial Pentose Phosphate Pathway Rates in Response to High-Glucose Environments

Brain aerobic glycolysis functions and Alzheimer’s disease

Energy Metabolism in the Brain

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