Brain biomolecules oxidation in portacaval-shunted rats

Carbonero-Aguilar, Pilar; Díaz-Herrero, María del Mar; Cremades, Olga; Romero‐Gómez, Manuel; Bautista, Juan

doi:10.1111/j.1478-3231.2011.02515.x

Cited by 15 publications

(8 citation statements)

References 27 publications

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“…In agreement with that, oxidized mRNA and decreased ribosomal rRNA and tRNA levels due to oxidation have been related to abnormal protein synthesis in post mortem cerebral tissue samples of patients with Alzheimer disease (Ding et al, 2005;Shan et al, 2003). Considering that increased oxidative stress is also a feature of chronic HE (Carbonero-Aguilar et al, 2011;Seyan et al, 2010), it is possible that part of the mRNA pool is oxidized in the cerebral cortex of BDL rats. It should also be considered that the protein levels of the astrocytic glutamine transporter might change depending on the cellular and cerebral structures.…”

Section: Discussionsupporting

confidence: 57%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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Rama Rao, Kakulavarapu V.; Silveira, Themis Reverbel; Norenberg, Michael D.; and Schousboe, Arne, "Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy" (2015 Keywords:Chronic hepatic encephalopathy Glutamine transporters Glutamine GABA A B S T R A C THepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.

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Section: Discussionsupporting

confidence: 57%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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“…; Singh and Trigun ; Carbonero‐Aguilar et al . ) (also see Table ) were added to astrocyte cultures for different time periods (1, 5, and 10 days with regular media changes, once in 2 days for both 5‐ and 10‐day treatment). At the end of treatment (24 h after the addition of last ammonia exposure), TSP‐1 protein levels in the cell extracts and culture media were measured by western blots.…”

Section: Resultsmentioning

confidence: 99%

Decreased astrocytic thrombospondin‐1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies

Jayakumar

Tong

Curtis

et al. 2014

Journal of Neurochemistry

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Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5–2.5 mM) for 1–10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media (CM) from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95 and synaptotagmin levels. CM from TSP-1 overexpressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE.

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“…Increased [Ca 2+ ] i also occurs in brain slices exposed to as little as 1-2 mM ammonia, and inhibition of GS results in a significantly larger [Ca 2+ ] increases [153], perhaps due to impaired ammonia detoxification. The reason for the delayed response at relative low ammonia concentrations is a gradually developing, marked nitrosative and oxidative damage after ammonia exposure [154][155][156][157] Fig. 5 Similarity between effects of ammonia (5 mM) on protein expression of both NKCC1 and phosphorylated NKCC1 (p-NKCC1) in cultured rat astrocytes (a1, a2) and the effect of thioacetamideinduced acute liver failure in rats in vivo, leading to hyperammonemia (b1, b2).…”

Section: Cyclic Gmp and Nitric Oxidementioning

confidence: 89%

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

et al. 2016

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Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH and K in their effects on the Na,K-ATPase and the Na,K, 2 Cl and water transporter NKCC1. Stimulation of the Na,K-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na,K-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.

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Brain biomolecules oxidation in portacaval-shunted rats

Cited by 15 publications

References 27 publications

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Decreased astrocytic thrombospondin‐1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

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