Homeostasis of glutamate in brain fluids: An accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies

Teichberg, Vivian I.; Malina, Katayun Cohen-Kashi; Cooper, Itzik; Zlotnik, Alexander

doi:10.1016/j.neuroscience.2008.02.075

Cited by 122 publications

(165 citation statements)

References 52 publications

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“…9 In addition, the present data suggest that promising therapeutic strategies characterized in adult models of stroke and head injuries, based on increasing glutamate efflux by enhancing the brain-to-blood gradient, may not be as effective in neonates. 5,15 In conclusion, our data provide new evidence of the molecular and functional specificities of immature endothelial cells with respect to EAAT expression and glutamate uptake. They reinforce the hypothesis of vascular involvement in both the developmental and pathologic effects of glutamate in the immature brain.…”

Section: Discussionmentioning

confidence: 56%

“…1 Accumulating evidence indicates that mature microvascular endothelial cells also express EAAT1-3. 5,6 In particular, brain endothelial cells appear to control extracellular glutamate concentrations by inducing the uptake and, subsequently, the efflux of glutamate across the blood-brain barrier. 7,8 To our knowledge, EAAT1-3 expression in neonatal endothelial cells has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

Lecointre

Hauchecorne

Chaussivert

et al. 2014

J Cereb Blood Flow Metab

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Glutamate transporters (excitatory amino-acid transporters (EAATs)) are essential for brain homeostasis. While previous studies indicate that the vascular endothelium contributes to glutamate efflux in the adult brain, little information is available regarding glutamate uptake in the immature brain. The present study shows a differential expression pattern of EAATs between cortical microvessels in adults and newborns. In addition, adult cortical endothelial cells take up glutamate more efficiently than neonatal cells. Our findings indicate age-specific changes in extracellular glutamate regulation by brain endothelial cells, suggesting differences in the efficiency of glutamate efflux during an excitotoxic process that, in turn, may contribute to age-specific brain vulnerability.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

Lecointre

Hauchecorne

Chaussivert

et al. 2014

J Cereb Blood Flow Metab

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“…According to this, the capacity of the enzyme glutamate oxaloacetate transaminase (GOT) to metabolize glutamate represents a strategy to decrease glutamate levels in blood (Gottlieb et al, 2003;Teichberg et al, 2009). In fact, we observed that oxaloacetate-mediated GOT activation in an animal model of ischemia induces a neuroprotective effect, thus showing this endogenous blood enzyme as a novel neuroprotective tool against ischemic stroke (Campos et al, 2011).…”

Section: Introductionmentioning

confidence: 95%

“…As ischemic stroke is associated with an excessive release of glutamate into the brain parenchyma (Castillo et al, 1996(Castillo et al, , 1997, a decrease in blood glutamate levels provides a mechanism to increase the gradient concentration and to remove this neurotransmitter from the brain at early times, with possible therapeutic implications after an ischemic insult (Gottlieb et al, 2003;Teichberg et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke

Campos

Sobrino

Blanco

et al. 2011

J Cereb Blood Flow Metab

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The capacity of the blood enzyme glutamate oxaloacetate transaminase (GOT) to remove glutamate from the brain by means of blood glutamate degradation has been shown in experimental models to be an efficient and novel neuroprotective tool against ischemic stroke; however, the beneficial effects of this enzyme should be tested in patients with stroke to validate these results. This study aims to investigate the association of GOT levels in blood with clinical outcome in patients with acute ischemic stroke. In two clinical independent studies, we found that patients with poor outcome show higher glutamate and lower GOT levels in blood at the time of admission. Lower GOT levels and higher glutamate levels were independently associated with poorer functional outcome at 3 months and higher infarct volume. These findings show a clear association between high blood glutamate levels and worse outcome and vice versa for GOT, presumably explained by the capacity of this enzyme to metabolize blood glutamate.

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“…The maintenance of brain extracellular Glu at levels below its excitotoxic threshold is performed not only by the Glu transporters located on glia and neurons but also by those present on the antiluminal side of the brain capillary endothelial cells [16, 17]. These transporters remove the excess extracellular brain Glu into blood [18, 19].…”

Section: Introductionmentioning

confidence: 99%

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

et al. 2012

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SummaryL-Glutamate (Glu) plays a crucial role in the growth of malignant gliomas. We have established the feasibility of accelerating a naturally occurring brain to-blood Glu efflux by decreasing blood Glu levels with intravenous oxaloacetate, the respective Glu co-substrate of the blood resident enzyme humane glutamate–oxaloacetate transaminase (hGOT). We wished to demonstrate that blood Glu scavenging provides neuroprotection in the case of glioma. We now describe the neuroprotective effects of blood Glu scavenging in a fatal condition such as brain-implanted C6 glioma in rats and brain-implanted human U87 MG glioma in nude mice. Rat (C-6) or human (U87) glioma cells were grafted stereotactically in the brain of rats or mice. After development of tumors, the animals were drinking oxaloacetate with or without injections of hGOT. In addition, mice were treated with combination treatment, which included drinking oxaloacetate with intracutaneous injections of hGOT and intraperitoneal injection of Temozolomide. Animals drinking oxaloacetate with or without injections of hGOT displayed a smaller tumor volume, reduced invasiveness and prolonged survival than control animals drinking saline. These effects were significantly enhanced by Temozolomide in mice, which increased survival by 237%. This is the first demonstration of blood Glu scavenging in brain cancer, and because of its safety, is likely to be of clinical significance for the future treatment of human gliomas. As we demonstrated, the blood glutamate scavenging treatment in combination with TMZ could be a good candidate or as an alternative treatment to the patients that do not respond to TMZ.

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Homeostasis of glutamate in brain fluids: An accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies

Cited by 122 publications

References 52 publications

The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

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