Arsenite stimulates glutathione export and glycolytic flux in viable primary rat brain astrocytes

Tadepalle, Nimesha; Koehler, Yvonne; Brandmann, Maria; Meyer, Nils; Dringen, Ralf

doi:10.1016/j.neuint.2014.06.013

Cited by 28 publications

(13 citation statements)

References 77 publications

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“…The observed acute stimulation by metformin of glycolytic flux in astrocytes adds metformin to a list of structurally diverse compounds which have previously been reported to acutely stimulate astrocytic lactate production under similar experimental conditions, including respiratory chain inhibitors [45], formaldehyde [46], arsenate [25], arsenite [47] or 8-hydroxyefavirenz [48]. However, in contrast to these compounds, the stimulating effect of metformin on astrocytic glycolysis was persistent as removal of extracellular metformin did not rapidly abolish the stimulated lactate release.…”

Section: Discussionmentioning

confidence: 67%

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

2015

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Metformin is the most frequently used drug for the treatment of type 2 diabetes in humans. However, only little is known about effects of metformin on brain metabolism. To investigate potential metabolic consequences of an exposure of brain cells to metformin, we incubated rat astrocyte-rich primary cultures with this compound. Metformin in concentrations of up to 30 mM did not acutely compromise the viability of astrocytes, but caused a time- and concentration-dependent increase in cellular glucose consumption and lactate production. For acute incubations in the hour range, the presence of 10 mM metformin doubled the glycolytic flux, while already 1 mM metformin doubled glycolytic flux during incubation for 24 h. In addition to metformin, also other guanidino compounds increased astrocytic lactate production. After 4 h of incubation, half-maximal stimulation of glycolysis was observed for metformin, guanidine and phenformin at concentrations of around 3 mM, 3 mM and 30 µM, respectively. The acute stimulation of glycolytic lactate production by metformin was persistent after removal of extracellular metformin and was also observed, if glucose was absent from the incubation medium or replaced by other hexoses. The metformin-induced stimulation of glycolytic flux was not prevented by compound C, an inhibitor of AMP-dependent protein kinase, nor was it additive to the stimulation of glycolytic flux caused by respiratory chain inhibitors. These data demonstrate that the antidiabetic drug metformin has the potential to strongly activate glycolytic lactate production in brain astrocytes.

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Section: Discussionmentioning

confidence: 67%

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

2015

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“…Recently a number of compounds have been reported to strongly stimulate rapid GSH export from viable astrocytes, including formaldehyde [96], arsenate and arsenite [97,98] and antiretroviral protease inhibitors [99,100]. Although all of these stimulated GSH export processes were almost completely prevented by inhibition of Mrp1, the molecular mechanism how such structurally very diverse compounds accelerate Mrp1-mediated GSH export remains unclear.…”

Section: Gsh Redox Cyclingmentioning

confidence: 99%

Glutathione-Dependent Detoxification Processes in Astrocytes

et al. 2014

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Astrocytes have a pivotal role in brain as partners of neurons in homeostatic and metabolic processes. Astrocytes also protect other types of brain cells against the toxicity of reactive oxygen species and are considered as first line of defence against the toxic potential of xenobiotics. A key component in many of the astrocytic detoxification processes is the tripeptide glutathione (GSH) which serves as electron donor in the GSH peroxidase-catalyzed reduction of peroxides. In addition, GSH is substrate in the detoxification of xenobiotics and endogenous compounds by GSH-S-transferases which generate GSH conjugates that are efficiently exported from the cells by multidrug resistance proteins. Moreover, GSH reacts with the reactive endogenous carbonyls methylglyoxal and formaldehyde to intermediates which are substrates of detoxifying enzymes. In this article we will review the current knowledge on the GSH metabolism of astrocytes with a special emphasis on GSH-dependent detoxification processes.

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“…BBB transporters that can transport GSH and GSSG include MRPs/Mrps. Both GSH and GSSG are substrates for MRP1/Mrp1 (Hirrlinger et al 2001; Hirrlinger and Dringen, 2005; Ronaldson and Bendayan, 2008; Tadepalle et al 2014), MRP2/Mrp2 (Paulusma et al 1999), and MRP4/Mrp4 (Rius et al 2006). In contrast, MRP5/Mrp5 is not involved in GSH and/or GSSG transport (Minich et al 2006).…”

Section: Targeting Endogenous Bbb Transportersmentioning

confidence: 99%

“…Therefore, it stands to reason that pharmacological targeting of Mrps during oxidative stress may have profound therapeutic benefits. Using the known Mrp transport inhibitor MK571, Tadepalle and colleagues showed that inhibition of Mrp1 -mediated GSH transport resulted prevented GSH depletion in primary cultures of rat astrocytes (Tadepalle et al 2014). Indeed, the effect of Mrp transport inhibition at the BBB and its effect on endothelial redox status and barrier integrity requires further study.…”

Section: Targeting Endogenous Bbb Transportersmentioning

confidence: 99%

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

Ronaldson

Davis

2015

Brain Research

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The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., endogenous transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress.

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Arsenite stimulates glutathione export and glycolytic flux in viable primary rat brain astrocytes

Cited by 28 publications

References 77 publications

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

Glutathione-Dependent Detoxification Processes in Astrocytes

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

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