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Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept.

Zielińska M, Popek M, Albrecht J - Neurochem. Res. (2013)

Bottom Line: Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis.Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects.TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego St. 5, 02-106, Warsaw, Poland, mzielinska@imdik.pan.pl.

ABSTRACT
Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood-brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan.

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Effect of the presence of 10 mM BCH, Leu and cyclo-Leu on [3H] Gln uptake in control and hyperammonemic (HA) rat cerebral cortical slices. Cerebral cortical slices of HA rat were pre-incubated for 30 min at 37 °C and the uptake was started by adding L-[3H] Gln (Perkin-Elmer) at 100 mmol/l final concentration and the incubation was continued for 4 min. The incubation was terminated by rapid vacuum filtration, followed by three washes with 2 ml with Krebs buffer maintained at 4 °C. The radioactivity on filter disks was measured in a liquid scintillation spectrometer. The control value for [3H] Gln uptake was 29.5 nmol/min/mg wet tissues. Values in each group are mean ± SD for n = 5. (*p < 0.05; Dunnet’s test)
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Fig1: Effect of the presence of 10 mM BCH, Leu and cyclo-Leu on [3H] Gln uptake in control and hyperammonemic (HA) rat cerebral cortical slices. Cerebral cortical slices of HA rat were pre-incubated for 30 min at 37 °C and the uptake was started by adding L-[3H] Gln (Perkin-Elmer) at 100 mmol/l final concentration and the incubation was continued for 4 min. The incubation was terminated by rapid vacuum filtration, followed by three washes with 2 ml with Krebs buffer maintained at 4 °C. The radioactivity on filter disks was measured in a liquid scintillation spectrometer. The control value for [3H] Gln uptake was 29.5 nmol/min/mg wet tissues. Values in each group are mean ± SD for n = 5. (*p < 0.05; Dunnet’s test)

Mentions: HA [3 i.p. injections of ammonium acetate (600 mg per kg) at 24 h intervals] decreased L-[3H] Gln uptake to the cerebral cortical slices, and the decrease affected the component of uptake sensitive to leucine (Leu), 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH), and cyclo-leucine, indicating selective vulnerability to system L (Fig. 1).Fig. 1


Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept.

Zielińska M, Popek M, Albrecht J - Neurochem. Res. (2013)

Effect of the presence of 10 mM BCH, Leu and cyclo-Leu on [3H] Gln uptake in control and hyperammonemic (HA) rat cerebral cortical slices. Cerebral cortical slices of HA rat were pre-incubated for 30 min at 37 °C and the uptake was started by adding L-[3H] Gln (Perkin-Elmer) at 100 mmol/l final concentration and the incubation was continued for 4 min. The incubation was terminated by rapid vacuum filtration, followed by three washes with 2 ml with Krebs buffer maintained at 4 °C. The radioactivity on filter disks was measured in a liquid scintillation spectrometer. The control value for [3H] Gln uptake was 29.5 nmol/min/mg wet tissues. Values in each group are mean ± SD for n = 5. (*p < 0.05; Dunnet’s test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3926979&req=5

Fig1: Effect of the presence of 10 mM BCH, Leu and cyclo-Leu on [3H] Gln uptake in control and hyperammonemic (HA) rat cerebral cortical slices. Cerebral cortical slices of HA rat were pre-incubated for 30 min at 37 °C and the uptake was started by adding L-[3H] Gln (Perkin-Elmer) at 100 mmol/l final concentration and the incubation was continued for 4 min. The incubation was terminated by rapid vacuum filtration, followed by three washes with 2 ml with Krebs buffer maintained at 4 °C. The radioactivity on filter disks was measured in a liquid scintillation spectrometer. The control value for [3H] Gln uptake was 29.5 nmol/min/mg wet tissues. Values in each group are mean ± SD for n = 5. (*p < 0.05; Dunnet’s test)
Mentions: HA [3 i.p. injections of ammonium acetate (600 mg per kg) at 24 h intervals] decreased L-[3H] Gln uptake to the cerebral cortical slices, and the decrease affected the component of uptake sensitive to leucine (Leu), 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH), and cyclo-leucine, indicating selective vulnerability to system L (Fig. 1).Fig. 1

Bottom Line: Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis.Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects.TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego St. 5, 02-106, Warsaw, Poland, mzielinska@imdik.pan.pl.

ABSTRACT
Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a "Trojan horse" mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y(+)LAT2. Gln export from brain across the blood-brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan.

Show MeSH
Related in: MedlinePlus