The Effect of Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome in a Rat Model of Subarachnoid Hemorrhage

Boyko, Matthew; Melamed, Israel; Gruenbaum, Benjamin F.; Gruenbaum, Shaun E.; Ohayon, Sharon; Leibowitz, Akiva; Brotfain, Evgeni; Shapira, Yoram; Zlotnik, Alexander

doi:10.1007/s13311-012-0129-6

Cited by 46 publications

(55 citation statements)

References 75 publications

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“…Furthermore, pyruvate is a 'neuroprotective' reagent, because it reacts non-enzymatically with reactive oxygen species 137 , and beneficial effects of pyruvate have been documented after TBI, subarachnoid hemorrhage, and glutamate excitotoxicity. [138][139][140][141][142] Infusion of lactate provides a continuous supply of pyruvate that may contribute to beneficial effects of lactate, but pyruvate itself may be the best choice as metabolic substrate and neuroprotective agent. Infusions of sodium pyruvate would, like sodium lactate, be limited by increased Na + levels in blood, and sodium pyruvate should help control increases in intracranial pressure.…”

Section: Pyruvate As An Alternative To Lactate After Traumatic Brain mentioning

confidence: 99%

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

Dienel

2014

J Cereb Blood Flow Metab

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Lactate is proposed to be generated by astrocytes during glutamatergic neurotransmission and shuttled to neurons as 'preferred' oxidative fuel. However, a large body of evidence demonstrates that metabolic changes during activation of living brain disprove essential components of the astrocyte-neuron lactate shuttle model. For example, some glutamate is oxidized to generate ATP after its uptake into astrocytes and neuronal glucose phosphorylation rises during activation and provides pyruvate for oxidation. Extension of the notion that lactate is a preferential fuel into the traumatic brain injury (TBI) field has important clinical implications, and the concept must, therefore, be carefully evaluated before implementation into patient care. Microdialysis studies in TBI patients demonstrate that lactate and pyruvate levels and lactate/pyruvate ratios, along with other data, have important diagnostic value to distinguish between ischemia and mitochondrial dysfunction. Results show that lactate release from human brain to blood predominates over its uptake after TBI, and strong evidence for lactate metabolism is lacking; mitochondrial dysfunction may inhibit lactate oxidation. Claims that exogenous lactate infusion is energetically beneficial for TBI patients are not based on metabolic assays and data are incorrectly interpreted.

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Section: Pyruvate As An Alternative To Lactate After Traumatic Brain mentioning

confidence: 99%

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

Dienel

2014

J Cereb Blood Flow Metab

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“…The use of blood glutamate scavengers effectively resulted in the elimination of excess glutamate in the brain ventricles and CSF (Gottlieb et al 2003), as well as from the brain parenchyma (Teichberg et al 2009), as evidenced with the use of dual-probe microdialysis experiments. Likewise, peripheral injections of GOT and GPT in naïve rats, as a single treatment modality and in combination with its co-substrates oxaloacetate and pyruvate, respectively, have been shown to result in a reduction in blood glutamate (Zlotnik et al 2007; Boyko et al 2012a, b). …”

Section: Blood Glutamate Scavenging With Oxaloacetate and Pyruvatementioning

confidence: 99%

“…In a rat model of SAH, oxaloacetate and pyruvate (250 and 125 mg/kg) were infused for 30, 60 min after induction of SAH (Boyko et al 2012a, b). Infusion of the scavengers was associated with a significant reduction in blood and CSF glutamate.…”

Section: Blood Glutamate Scavenging With Oxaloacetate and Pyruvatementioning

confidence: 99%

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Brain to blood glutamate scavenging as a novel therapeutic modality: a review

Boyko

Gruenbaum

et al. 2014

J Neural Transm

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It is well known that abnormally elevated glutamate levels in the brain are associated with secondary brain injury following acute and chronic brain insults. As such, a tight regulation of brain glutamate concentrations is of utmost importance in preventing the neurodegenerative effects of excess glutamate. There has been much effort in recent years to better understand the mechanisms by which glutamate is reduced in the brain to non-toxic concentrations, and in how to safely accelerate these mechanisms. Blood glutamate scavengers such as oxaloacetate, pyruvate, glutamate–oxaloacetate transaminase, and glutamate-pyruvate transaminase have been shown to reduce blood glutamate concentrations, thereby increasing the driving force of the brain to blood glutamate efflux and subsequently reducing brain glutamate levels. In the past decade, blood glutamate scavengers have gained increasing international interest, and its uses have been applied to a wide range of experimental contexts in animal models of traumatic brain injury, ischemic stroke, subarachnoid hemorrhage, epilepsy, migraine, and malignant gliomas. Although glutamate scavengers have not yet been used in humans, there is increasing evidence that their use may provide effective and exciting new therapeutic modalities. Here, we review the laboratory evidence for the use of blood glutamate scavengers. Other experimental neuro-protective treatments thought to scavenge blood glutamate, including estrogen and progesterone, beta-adrenergic activation, hypothermia, insulin and glucagon, and hemodialysis and peritoneal dialysis are also discussed. The evidence reviewed here will hopefully pave the way for future clinical trials.

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“…In rats, treatment should be applied within a short timeframe, no later than 60 min after the onset of the excitotoxic event. In humans there is a longer time course of the ischemic insult following traumatic brain injury, and it has been suggested that a therapeutic treatment thus might be beneficial also at later stages (56). Introducing oxaloacetate as a therapeutic agent may also pose some challenges as its safety profile has not been investigated (16).…”

Section: Studies Of Glutamate Scavengers and Brain Glutamate Concentrmentioning

confidence: 99%

Glutamate Efflux at the Blood–Brain Barrier: Cellular Mechanisms and Potential Clinical Relevance

Helms

Nielsen

Brodin

2014

Archives of Medical Research

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The Effect of Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome in a Rat Model of Subarachnoid Hemorrhage

Cited by 46 publications

References 75 publications

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

Brain to blood glutamate scavenging as a novel therapeutic modality: a review

Glutamate Efflux at the Blood–Brain Barrier: Cellular Mechanisms and Potential Clinical Relevance

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