Brain neuroprotection by scavenging blood glutamate

Zlotnik, Alexander; Gurevich, Vsevolod V.; Tkachov, Sergei; Maoz, Ilana; Shapira, Yoram; Teichberg, Vivian I.

doi:10.1016/j.expneurol.2006.08.021

Cited by 101 publications

(166 citation statements)

References 45 publications

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“…On the strength of the fact that the administration of exogenous GOT transforms an ineffective low dose of OxAc into an effective one [22], we added hGOT to the treatment in order to elevate the blood GOT levels and possibly improve the effectiveness of oral OxAc for the scavenging of blood Glu. As temozolomide (TMZ) is a standard treatment of glioma, we also determined the anti-tumor effects of OxAc/hGOT, TMZ and their combination.…”

Section: Resultsmentioning

confidence: 99%

“…We later demonstrated that blood Glu scavenging provides highly significant brain neuroprotection since both OxAc and pyruvate improve the neurological status of rats submitted to close head injury [20–22]. …”

Section: Introductionmentioning

confidence: 99%

“…This combination is required both for the administration of realistic concentrations of OxAc and for the fact that the basal GOT levels in blood are limiting [22]. In our previous studies, we intravenously injected rats with OxAc to reach a steady state concentration in blood [19].…”

Section: Introductionmentioning

confidence: 99%

“…However, one can maintain (as expected from the Michaelis-Menten equation) the same rate of blood Glu transamination by reducing significantly the concentration of the administered OxAc while increasing in parallel the GOT blood concentration. Using this approach, we found [22] that an optimal blood Glu scavenging and neuroprotection after TBI could be attained by administering 1 ml of 10 mM OxAc/100 g rat (this dose is ineffective on its own) together with 13 μg recombinant GOT. Increasing the GOT concentration in blood facilitates the OxAc-mediated blood Glu scavenging since it allows the intravenously administered OxAc to readily react with the transaminase before being transported into the various body organs via the dicarboxylate transporters [27, 28].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…In experimental models, the capacity of the enzyme GOT to remove glutamate from the brain by means of blood glutamate degradation has been shown to be an efficient and novel neuroprotective strategy against ischemic damage; however, the beneficial effects of this enzyme have not yet been tested in stroke patients (Gottlieb et al, 2003;Teichberg et al, 2009;Zlotnik et al, 2007).…”

Section: Discussionmentioning

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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Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients

Vidoni

Choi

Lee

et al. 2020

Alzheimer's & Dementia

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Introduction: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. Methods: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. Results: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. Conclusions: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.

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Brain neuroprotection by scavenging blood glutamate

Cited by 101 publications

References 45 publications

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

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

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

Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients

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