Neuroprotective Effect of Oxaloacetate in a Focal Brain Ischemic Model in the Rat

Knapp, Levente; Gellért, Levente; Kocsis, Krisztián; Kis, Zsolt; Farkas, Tamás; Vécsei, László; Toldi, József

doi:10.1007/s10571-014-0064-7

Cited by 19 publications

(13 citation statements)

References 28 publications

(32 reference statements)

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“…The ischemic-like cell death is also called oncosis and has been shown to be involved in diseases such as ischemic heart disease and stroke [ 37 – 39 ]. Consistent with our results, other studies have shown that OAA is neuroprotective against ischemic stroke and that a combination of human rGOT1 with low doses of OAA induces a protective effect after cerebral ischemia [ 40 , 41 ]. Moreover, evidence also indicates that NAD + is able to protect cells against ischemic injury [ 42 , 43 ].…”

Section: Discussionsupporting

confidence: 92%

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

Zhou

Curbo

Li³

et al. 2018

BMC Cancer

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BackgroundGlutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements. KRAS mutated cancer cells were recently shown to rely on GOT1 to support long-term cell proliferation. The aim of the present study was to address the role of GOT1 in the metabolic adaption of cancer cells.MethodsGOT1-null and knockdown cell lines were established through CRISPR/Cas9 and shRNA techniques. The growth properties, colony formation ability, autophagy and selected gene expression profiles were analysed. Glucose deprivation decreased the viability of the GOT1-null cells and rescue experiments were conducted with selected intermediates. The redox NADH/NAD+ homeostasis as well as lactate secretion were determined. GOT1 expression levels and correlation with survival rates were analysed in selected tumor databases.ResultsInhibition of GOT1 sensitized the cancer cells to glucose deprivation, which was partially counteracted by oxaloacetate and phosphoenol pyruvate, metabolic intermediates downstream of GOT1. Moreover, GOT1-null cells accumulated NADH and displayed a decreased ratio of NADH/NAD+ with nutrient depletion. The relevance of GOT1 as a potential target in cancer therapy was supported by a lung adenocarcinoma RNA-seq data set as well as the GEO:GSE database of metastatic melanoma where GOT1 expression was increased. High levels of GOT1 were further linked to poor survival as analysed by the GEPIA web tool, in thyroid and breast carcinoma and in lung adenocarcinoma.ConclusionsOur study suggests an important role of GOT1 to coordinate the glycolytic and the oxidative phosphorylation pathways in KRAS mutated cancer cells. GOT1 is crucial to provide oxaloacetate at low glucose levels, likely to maintain the redox homeostasis. Our data suggest GOT1 as a possible target in cancer therapy.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4443-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

Zhou

Curbo

Li³

et al. 2018

BMC Cancer

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“…14,15,17,31 This novel mechanism has also been validated for other independent laboratories with similar results. 16,32,33 However, despite the beneficial effect observed in ischemic stroke models and other neurologic disorder animal models, in this study, administration of two of the most efficient blood glutamate grabbers used (oxaloacetate or rGOT1) was not able to reduce hematoma lesion or improve the neurologic outcome in animals subjected to an ICH. Reduction of blood glutamate levels showed that both drugs had indeed an effect on lowering blood and subsequently brain glutamate levels.…”

Section: Discussioncontrasting

confidence: 66%

Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

Silva‐Candal

Vieites‐Prado

Gutiérrez-Fernández

et al. 2015

J Cereb Blood Flow Metab

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Recent studies have shown that blood glutamate grabbing is an effective strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. The purpose of the study was to investigate the effect of two of the most efficient blood glutamate grabbers (oxaloacetate and recombinant glutamate oxaloacetate transaminase 1: rGOT1) in a rat model of intracerebral hemorrhage (ICH). Intracerebral hemorrhage was produced by injecting collagenase into the basal ganglia. Three treatment groups were developed: a control group treated with saline, a group treated with oxaloacetate, and a final group treated with human rGOT1. Treatments were given 1 hour after hemorrhage. Hematoma volume (analyzed by magnetic resonance imaging (MRI)), neurologic deficit, and blood glutamate and GOT levels were quantified over a period of 14 days after surgery. The results observed showed that the treatments used induced a significant reduction of blood glutamate levels; however, they did not reduce the hematoma, nor did they improve the neurologic deficit. In the present experimental study, we have shown that this novel therapeutic strategy is not effective in case of ICH pathology. More importantly, these findings suggest that blood glutamate grabbers are a safe treatment modality that can be given in cases of suspected ischemic stroke without previous neuroimaging. Keywords: blood glutamate grabbing; GOT; intracerebral hemorrhage; oxaloacetate; protection INTRODUCTION Intracerebral hemorrhage (ICH) represents approximately 15% of all strokes; moreover, the incidence of ICH is expected to grow, given the increase in the use of anticoagulants and aging of the population. Journal of Cerebral Blood1 It is a type of acute stroke characterized by extravasation of blood into the brain parenchyma and formation of hematoma. Hematoma produces primary damage because of the toxic effect of thrombin, a mass effect due to the extravasated blood that compresses the surrounding brain tissue; sometimes, this damage is also enhanced by rebleeding. Primary damage is followed by a secondary damage mainly characterized by edema formation, tissular ischemia, and glutamate excitotoxicity.

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“…To confirm that the neuroprotective effect was due to a decrease in brain glutamate levels, spectroscopic analysis revealed that the increase in brain glutamate observed in control animals after MCAO was clearly reduced in animals treated with OxAc. These results were also validated by other independent laboratories 15 .…”

Section: Blood To Brain Glutamate Grabbingsupporting

confidence: 75%

Beyond Glutamate Antagonists for Treatment of Ischemic Stroke: Blood Glutamate Grabbing

Castillo¹

2016

J Neurol Neuromedicine

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Glutamate-excitotoxicity is a primary contributor of ischemic neuronal death. Several strategies have been developed against glutamate-excitotoxicity, however any of them have not showed positive results in the clinical practice so far.Nowadays, the concept of blood/brain glutamate grabbing is well recognized as a novel and attractive protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain following an ischemic stroke. The main advantage of this novel therapeutic strategy is that occurs in the blood circulation and therefore does not affect the normal brain neurophysiology, as it has been described for other drug treatments used against glutamate excitotoxicity. In this work, we summarize all experimental data about the potential application of this therapy against stroke pathology.

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Neuroprotective Effect of Oxaloacetate in a Focal Brain Ischemic Model in the Rat

Cited by 19 publications

References 28 publications

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

Beyond Glutamate Antagonists for Treatment of Ischemic Stroke: Blood Glutamate Grabbing

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