Methylene blue stimulates 2-deoxyglucose uptake in L929 fibroblast cells

Louters, Larry L.; Dyste, Samuel G.; Frieswyk, Deborah; TenHarmsel, Aaron; Kooy, Tim O. Vander; Walters, Lindsey; Whalen, Teresa

doi:10.1016/j.lfs.2005.05.082

Cited by 24 publications

(35 citation statements)

References 23 publications

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“…The CMRO 2 increases resulted mainly from elevated oxygenation (i.e., increased CBF) rather than from oxygen extraction (i.e., OEF), because CBF dramatically increased, whereas OEF remained unchanged. The finding of MB-evoked increases in glucose uptake was in good agreement with literature findings that MB can stimulate glucose metabolism, possibly via a single glucose transporter, GLUT1 [23]. Taken together, the increases in CMRO 2 and glucose uptake suggest that MB can elevate oxygen consumption for the oxidative phosphorylation of glucose to increase ATP production [10].…”

Section: Discussionsupporting

confidence: 90%

Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

Lin

Poteet

et al. 2012

PLoS ONE

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By restoring mitochondrial function, methylene blue (MB) is an effective neuroprotectant in many neurological disorders (e.g., Parkinson’s and Alzheimer’s diseases). MB has also been proposed as a brain metabolic enhancer because of its action on mitochondrial cytochrome c oxidase. We used in vitro and in vivo approaches to determine how MB affects brain metabolism and hemodynamics. For in vitro, we evaluated the effect of MB on brain mitochondrial function, oxygen consumption, and glucose uptake. For in vivo, we applied neuroimaging and intravenous measurements to determine MB’s effect on glucose uptake, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) under normoxic and hypoxic conditions in rats. MB significantly increases mitochondrial complex I–III activity in isolated mitochondria and enhances oxygen consumption and glucose uptake in HT-22 cells. Using positron emission tomography and magnetic resonance imaging (MRI), we observed significant increases in brain glucose uptake, CBF, and CMRO2 under both normoxic and hypoxic conditions. Further, MRI revealed that MB dramatically increased CBF in the hippocampus and in the cingulate, motor, and frontoparietal cortices, areas of the brain affected by Alzheimer’s and Parkinson’s diseases. Our results suggest that MB can enhance brain metabolism and hemodynamics, and multimetric neuroimaging systems offer a noninvasive, nondestructive way to evaluate treatment efficacy.

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Section: Discussionsupporting

confidence: 90%

Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

Lin

Poteet

et al. 2012

PLoS ONE

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“…In addition, there is accumulating evidence indicating that activity of GLUT1 can be acutely activated by cell stress. Studies in cells that express GLUT1 reveal that short-term exposure to cell stressors such as hypoxia, hyperosmolarity, respiration inhibitors, and glucose deprivation all activate glucose uptake [21][22][23][24][25]. The data reported here reveal for the first time that verapamil inhibits the glucose transport activity of GLUT1 in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 77%

“…Glucose uptake was determined from the amount of 3 H-2-DG radioactivity isolated with the cells after subtracting out the extracellular 3 H-2-DG. The extracellular 3 H-2-DG was determined from the amount of 14 C mannitol (not transported in these cells) that was also isolated with the cells [22,23,28].…”

Section: Methodsmentioning

confidence: 99%

“…For GLUT4, it has been well established that both exercise and insulin stimulate glucose uptake by an enhanced translocation of GLUT4 from internal stores to the cell surface membrane. GLUT1, on the other hand, is generally not sensitive to insulin or exercise, but can be activated within minutes by cell stressors such as hypoxia, hypoosmolarity, respiratory inhibitors, and glucose deprivation [20][21][22][23][24][25]. The mechanism of this activation is not well understood, but it is clear that it is not caused by a translocation of GLUT1 to the surface [20,22].…”

Section: Introductionmentioning

confidence: 99%

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Verapamil Inhibits the Glucose Transport Activity of GLUT1

et al. 2010

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Calcium channel blocker toxicity has been associated with marked hyperglycemia responsive only to high-dose insulin therapy. The exact mechanism(s) of this induced hyperglycemia has not been clearly delineated. The glucose transporter GLUT1 is expressed in a wide variety of cell types and is largely responsible for a basal level of glucose transport. GLUT1 also is activated by cell stress. The specific purpose of this study was to investigate the effects of the calcium channel blocker verapamil on the glucose uptake activity of GLUT1 in L929 fibroblasts cells. Dose-dependent effects of verapamil on glucose uptake were studied using L929 fibroblast cells with 2-deoxyglucose. Verapamil had a dose-dependent inhibitory effect on both basal and stress-activated transport activity of GLUT1. Basal activity was inhibited 50% by 300 μM verapamil, while 150 μM verapamil completely inhibited the activation induced by the stress of glucose deprivation. These effects were reversible and required verapamil to be present during the stress. Alteration of calcium concentrations by addition of 5 mM CaCl₂ or 4 mM EDTA had no effect on verapamil action. This study reveals the unique finding that verapamil has inhibitory effects on the transport activity of GLUT1 independent of its effects on calcium concentrations. The inhibition of GLUT1 may be one of the contributing factors to the hyperglycemia observed in CCB poisoning.

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“…The stimulating effect of MB on mitochondrial electron transport is in line with its action on glucose metabolism. In fibroblast cells, MB has been shown to stimulate 2-deoxyglucose uptake (Louters et al , 2006; Roelofs et al , 2006). Using MRI and PET, we demonstrated that acute treatment of MB significantly enhance glucose uptake and increase regional CBF in rats (Lin et al , 2012).…”

Section: Energy Metabolism and Cancersmentioning

confidence: 99%

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Yang

Sumien

et al. 2017

Progress in Neurobiology

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Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer’s, Parkinson’s and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicate that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome C, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer’s, Parkinson’s, and Huntington’s disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

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Methylene blue stimulates 2-deoxyglucose uptake in L929 fibroblast cells

Cited by 24 publications

References 23 publications

Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer

Verapamil Inhibits the Glucose Transport Activity of GLUT1

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

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