Rapid loss of glutamine synthetase from astrocytes in response to hypoxia: Implications for excitotoxicity

Lee, Aven; Lingwood, Barbara E.; Björkman, S. T.; Miller, Stephanie M.; Poronnik, Philip; Barnett, Nigel L.; Colditz, Paul B.; Pow, David V.

doi:10.1016/j.jchemneu.2009.12.002

Cited by 38 publications

(23 citation statements)

References 30 publications

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“…Moreover, there is an increase in metabolic activity in the liver since arginase was profoundly increased. Arginase is involved in the last step of the urea cycle in which toxic ammonia is converted to urea, which takes place in the cytoplasm of the liver [57,58,59]. We suggest that the increase in hepatic arginase could be used as a marker for increased hepatic metabolism after HI.…”

Section: Discussionmentioning

confidence: 99%

Cerebral and Hepatic Inflammatory Response after Neonatal Hypoxia-Ischemia in Newborn Rats

Bonestroo¹,

Nijboer²,

Velthoven³

et al. 2013

Dev Neurosci

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Background: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. Methods: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. Results: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1β and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1β, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1β expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-β expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. Conclusion: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-β together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but i...

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Section: Discussionmentioning

confidence: 99%

Cerebral and Hepatic Inflammatory Response after Neonatal Hypoxia-Ischemia in Newborn Rats

Bonestroo¹,

Nijboer²,

Velthoven³

et al. 2013

Dev Neurosci

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“…With few exceptions, glutamine synthetase activity is either restored or increased following ischemia and during [82] Shown are the effects of various stroke models on glutamine synthetase specific activity, amounts, and where measured: mRNA. The amounts of glutamine were determined by specific activity measurements (reported as activity in the table), electron microscopy (EM), Western blotting (WB), and immunohistochemistry (IMH).…”

Section: Glutamine Synthetase and Strokementioning

confidence: 99%

“…The amounts of glutamine were determined by specific activity measurements (reported as activity in the table), electron microscopy (EM), Western blotting (WB), and immunohistochemistry (IMH). No change, increases or decreases are indicated by blue, green and red lettering, respectively a References Neurochem Res reperfusion [63,64,[72][73][74][75][76][77][78][79][80][81][82] (Table 1). These changes occurred notwithstanding the production of both the Á NO and hydroxyl radicals as measured directly by EPR [67,68] and indirectly by other measures [64,73,75,76,[78][79][80][81].…”

Section: Glutamine Synthetase and Strokementioning

confidence: 99%

Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke

2015

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The following article addresses some seemingly paradoxical observations concerning cerebral glutamine synthetase in ischemia-reperfusion injury. In the brain, this enzyme is predominantly found in astrocytes and catalyzes part of the glutamine-glutamate cycle. Glutamine synthetase is also thought to be especially sensitive to inactivation by the oxygen- and nitrogen-centered radicals generated during strokes. Despite this apparent sensitivity, glutamine synthetase specific activity is elevated in the affected tissues during reperfusion. Given the central role of the glutamine-glutamate cycle in the brain, we sought to resolve these conflicting observations with the view of providing an alternative perspective for therapeutic intervention in stroke.

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“…Notably, gene deletion, gene knockdown, and pharmacological studies have indicated that the glutamate transporter-1 (GLT-1) subtype may contribute up to 90% of total transport in the forebrain, while inhibition of GLT-1 leads to severe neurological deficits and larger infarction volume (10,11). Furthermore, the intracellular glutamate is degraded by glutamine synthetase (GS), which accelerates glutamate transportation (12 of GS significantly impaired glutamate uptake and resulted in increased excitotoxicity to neurons (13). Therefore, GLT-1 and GS contribute to glutamate metabolism collectively.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of glutamate metabolism by BYHWD in cultured astrocytes following oxygen-glucose deprivation/reoxygenation in part depends on the activation of p38 MAPK

Guan

Zhou

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Recent studies have demonstrated that Buyang Huanwu Decoction (BYHWD) decreased glutamate levels subsequent to cerebral ischemia. Glutamate transporter-1 (GLT-1) and glutamine synthetase (GS), which are located in astrocytes, mainly contribute to glutamate transportation, thus reducing glutamate concentration. BYHWD has previously been demonstrated to upregulate GLT-1 and GS following ischemia in vivo. However, whether BYHWD can directly influence astrocytic GLT-1/GS levels remains unknown. In the present study, the effect of BYHWD containing serum (BYHWD-CS) on GLT-1/GS levels in astrocytes following oxygen-glucose deprivation/reoxygenation (OGD/R) was investigated. The results revealed that BYHWD-CS enhanced the expression levels of GLT-1 and GS in cultured astrocytes, which reduced glutamate concentration in the culture medium. Meanwhile, increased p38 mitogen-activated protein kinase (p38 MAPK) was phosphorylated (activation form) by BYHWD-CS in cultured astrocytes, and the specific p38 inhibitor SB203580 blocked the increase of GLT-1/GS accompanied by decreased cell viability. Furthermore, SB203580 suppressed the effect of BYHWD-CS on the level of glial fibrillary acidic protein (an astrocytic marker), thus confirming that astrocytes are directly involved in the protective role of BYHWD after OGD/R. These findings suggest that BYHWD upregulates GLT-1 and GS via p38 MAPK activation, and protects cultured astrocytes from death caused by OGD/R (typical in vitro model), which complemented the role of astrocytes in the protective effect of BYHWD.

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Rapid loss of glutamine synthetase from astrocytes in response to hypoxia: Implications for excitotoxicity

Cited by 38 publications

References 30 publications

Cerebral and Hepatic Inflammatory Response after Neonatal Hypoxia-Ischemia in Newborn Rats

Cerebral and Hepatic Inflammatory Response after Neonatal Hypoxia-Ischemia in Newborn Rats

Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke

Upregulation of glutamate metabolism by BYHWD in cultured astrocytes following oxygen-glucose deprivation/reoxygenation in part depends on the activation of p38 MAPK

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