Blood Glutamate Scavenging Research Articles

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-traumatic brain injury anxiety and social impairment

Traumatic brain injury (TBI) is a serious condition that is associated with an increased risk of severe, long-term psychiatric consequences. Drugs that target the glutamatergic system have proven successful in treating both TBI and many of its psychiatric sequelae. Blood glutamate scavengers (BGS) cause a decrease in blood glutamate levels, leading to a reduction in glutamate’s concentration gradient from the brain to the blood and decreased levels of brain glutamate. This study evaluated the BGS pyruvate as a treatment for TBI-related neuropsychiatric conditions in a rat model. 213 rats were divided into four groups in a 2 × 2 design: Sham or TBI rats treated with pyruvate or control treatment. Magnetic resonance imaging, neurological status, brain glutamate and blood glutamate levels were assessed following the injury. Four weeks after the start of treatment, all rats underwent behavioral tests to assess anxious behavior and social impairment (aggressive and hierarchical behavior). Rats responded positively to pyruvate in several tasks, lowering brain glutamate levels and reducing anxiety and depression, as well as modulating TBI-related changes in social behavior. Glutamate scavenging with pyruvate may be an effective therapeutic option for post-TBI behavioral changes by reducing associated elevations in brain glutamate levels.

Glutamate Efflux across the Blood–Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System

Depression is a significant cause of disability and affects millions worldwide; however, antidepressant therapies often fail or are inadequate. Current medications for treating major depressive disorder can take weeks or months to reach efficacy, have troubling side effects, and are limited in their long-term capabilities. Recent studies have identified a new set of glutamate-based approaches, such as blood glutamate scavengers, which have the potential to provide alternatives to traditional antidepressants. In this review, we hypothesize as to the involvement of the glutamate system in the development of depression. We identify the mechanisms underlying glutamate dysregulation, offering new perspectives on the therapeutic modalities of depression with a focus on its relationship to blood–brain barrier (BBB) permeability. Ultimately, we conclude that in diseases with impaired BBB permeability, such as depression following stroke or traumatic brain injury, or in neurogenerative diseases, the glutamate system should be considered as a pathway to treatment. We propose that drugs such as blood glutamate scavengers should be further studied for treatment of these conditions.

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model.

Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.

Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo

Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuating glioblastoma progression by reducing brain Glu levels. Therefore, in this study we evaluated the ability of BGS treatment to inhibit brain metastatic melanoma progression in-vivo. RET melanoma cells were implanted in C56BL/6J mice to induce brain melanoma tumors followed by treatment with BGS or vehicle administered for fourteen days. Bioluminescent imaging was conducted to evaluate tumor growth, and plasma/CSF Glu levels were monitored throughout. Immunofluorescence staining of Ki67 and 53BP1 was used to analyze tumor cell proliferation and DNA double-strand breaks. In addition, we analyzed CD8, CD68, CD206, p-STAT1 and iNOS expression to evaluate alterations in tumor micro-environment and anti-tumor immune response due to treatment. Our results show that BGS treatment reduces CSF Glu concentration and consequently melanoma growth in-vivo by decreasing tumor cell proliferation and increasing pro-apoptotic signaling in C56BL/6J mice. Furthermore, BGS treatment supported CD8+ cell recruitment and CD68+ macrophage invasion. These findings suggest that BGS can be of potential therapeutic relevance in the treatment of metastatic melanoma.

Blood glutamate scavengers and exercises as an effective neuroprotective treatment in mice with spinal cord injury.

Excitotoxicity due to neuronal damage and glutamate release is one of the first events that leads to the progression of neuronal degeneration and functional impairment. This study is based on a paradigm shift in the therapeutic approach for treating spinal cord injury (SCI). The authors tested a new treatment targeting removal of CNS glutamate into the blood circulation by injection of the blood glutamate scavengers (BGSs) recombinant enzyme glutamate-oxaloacetate transaminase (rGOT1) and its cosubstrate oxaloacetic acid (OxAc). Their primary objective was to investigate whether BGS treatment, followed by treadmill exercises in mice with SCI, could attenuate excitotoxicity, inflammation, scarring, and axonal degeneration and, at a later time point, improve functional recovery. A pharmacokinetic experiment was done in C57BL/6 naive mice to verify rGOT1/OxAc blood activity and to characterize the time curve of glutamate reduction in the blood up to 24 hours. The reduction of glutamate in CSF after BGS administration in mice with SCI was confirmed by high-performance liquid chromatography. Next, SCI (left hemisection) was induced in the mice, and the mice were randomly assigned to one of the following groups at 1 hour postinjury: control (underwent SCI and received PBS), treadmill exercises, rGOT1/OxAc treatment, or rGOT1/OxAc treatment followed by treadmill exercises. Treatment started 1 hour postinjury with an injection of rGOT1/OxAc and continued for 5 consecutive days. Starting 1 week after SCI, the exercises and the combined treatment groups recommenced the treadmill exercise regimen 5 days a week for 3 months. Locomotor function was assessed for 3 months using the horizontal grid walking test and CatWalk. Axonal anterograde and wallerian degenerations were evaluated using tetramethylrhodamine dextran. Tissue sections were immunofluorescently stained for Iba1, GFAP, GAP-43, synaptophysin, and NeuN. BGS treatment decreased the CSF glutamate level up to 50%, reduced axonal wallerian degeneration, and increased axonal survival and GAP-43 expression in neuronal cells. Combined treatment reduced inflammation, scarring, and lesion size. Additionally, the combination of BGS treatment and exercises increased synapses around motor neurons and enhanced axonal regeneration through the lesion site. This resulted in motor function improvement 3 months post-SCI. As shown by biochemical, immunohistochemical, and functional analysis, BGSs exhibit a substantial neuroprotective effect by reducing excitotoxicity and secondary damage after SCI. Furthermore, in combination with exercises, they reduced axonal degeneration and scarring and resulted in improved functional recovery.

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-stroke depression

Post-stroke depression (PSD) is a major complication of stroke that significantly impacts functional recovery and quality of life. While the exact mechanism of PSD is unknown, recent attention has focused on the association of the glutamatergic system in its etiology and treatment. Minimizing secondary brain damage and neuropsychiatric consequences associated with excess glutamate concentrations is a vital part of stroke management. The blood glutamate scavengers, oxaloacetate and pyruvate, degrade glutamate in the blood to its inactive metabolite, 2-ketoglutarate, by the coenzymes glutamate–oxaloacetate transaminase (GOT) and glutamate–pyruvate transaminase (GPT), respectively. This reduction in blood glutamate concentrations leads to a subsequent shift of glutamate down its concentration gradient from the blood to the brain, thereby decreasing brain glutamate levels. Although there are not yet any human trials that support blood glutamate scavengers for clinical use, there is increasing evidence from animal research of their efficacy as a promising new therapeutic approach for PSD. In this review, we present recent evidence in the literature of the potential therapeutic benefits of blood glutamate scavengers for reducing PSD and other related neuropsychiatric conditions. The evidence reviewed here should be useful in guiding future clinical trials.

Glutamate, T cells and multiple sclerosis.

Glutamate is the major excitatory neurotransmitter in the nervous system, where it induces multiple beneficial and essential effects. Yet, excess glutamate, evident in a kaleidoscope of acute and chronic pathologies, is absolutely catastrophic, since it induces excitotoxicity and massive loss of brain function. Both the beneficial and the detrimental effects of glutamate are mediated by a large family of glutamate receptors (GluRs): the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs), expressed by most/all cells of the nervous system, and also by many non-neural cells in various peripheral organs and tissues. T cells express on their cell surface several types of functional GluRs, and so do few other immune cells. Furthermore, glutamate by itself activates resting normal human T cells, and induces/elevates key T cell functions, among them: T cell adhesion, chemotactic migration, cytokine secretion, gene expression and more. Glutamate has also potent effects on antigen/mitogen/cytokine-activated T cells. Furthermore, T cells can even produce and release glutamate, and affect other cells and themselves via their own glutamate. Multiple sclerosis (MS) and its animal model Experimental Autoimmune Encephalomyelitis (EAE) are mediated by autoimmune T cells. In MS and EAE, there are excess glutamate levels, and multiple abnormalities in glutamate degrading enzymes, glutamate transporters, glutamate receptors and glutamate signaling. Some GluR antagonists block EAE. Enhancer of mGluR4 protects from EAE viaregulatory T cells (Tregs), while mGluR4 deficiency exacerbates EAE. The protective effect of mGluR4 on EAE calls for testing GluR4 enhancers in MS patients. Oral MS therapeutics, namely Fingolimod, dimethyl fumarate and their respective metabolites Fingolimod-phosphate and monomethyl fumarate, can protect neurons against acute glutamatergic excitotoxic damage. Furthermore, Fingolimod reduce glutamate-mediated intracortical excitability in relapsing-remitting MS. Glatiramer acetate -COPAXONE®, an immunomodulator drug for MS, reverses TNF-α-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents in EAE-afflicted mice. With regard to T cells of MS patients: (1) The cell surface expression of a specific GluR: the AMPA GluR3 is elevated in T cells of MS patients during relapse and with active disease, (2) Glutamate and AMPA (a selective agonist for glutamate/AMPA iGluRs) augment chemotactic migration of T cells of MS patients, (3) Glutamate augments proliferation of T cells of MS patients in response to myelin-derived proteins: MBP and MOG, (4) T cells of MS patients respond abnormally to glutamate, (5) Significantly higher proliferation values in response to glutamate were found in MS patients assessed during relapse, and in those with gadolinium (Gd)+ enhancing lesions on MRI. Furthermore, glutamate released from autoreactive T cells induces excitotoxic cell death of neurons. Taken together, the evidences accumulated thus far indicate that abnormal glutamate levels and signaling in the nervous system, direct activation of T cells by glutamate, and glutamate release by T cells, can all contribute to MS. This may be true also to other neurological diseases. It is postulated herein that the detrimental activation of autoimmune T cells by glutamate in MS could lead to: (1) Cytotoxicityin the CNS: T cell-mediated killing of neurons and glia cells, which would subsequently increase the extracellular glutamate levels, and by doing so increase the excitotoxicitymediated by excess glutamate, (2) Release of proinflammatory cytokines, e.g., TNFα and IFNγ that increase neuroinflammation. Finally, if excess glutamate, abnormal neuronal signaling, glutamate-induced activation of T cells, and glutamate release by T cells are indeed all playing a key detrimental role in MS, then optional therapeutic tolls include GluR antagonists, although these may have various side effects. In addition, an especially attractive therapeutic strategy is the novel and entirely different therapeutic approach to minimize excess glutamateand excitotoxicity, titled: 'brain to blood glutamate scavenging', designed to lower excess glutamate levels in the CNS by 'pumping it out' from the brain to the blood. The glutamate scavanging is achieved by lowering glutamate levels in the blood by intravenous injection of the blood enzyme glutamate oxaloacetate transaminase (GOT). The glutamate-scavenging technology, which is still experimental, validated so far for other brain pathologies,but not tested on MS or EAE yet, may be beneficial for MS too, since it could decrease both the deleterious effects of excess glutamate on neural cells, and the activation of autoimmune T cells by glutamate in the brain. The topic of glutamate scavenging, and also its potential benefit for MS, are discussed towards the end of the review, and call for research in this direction.

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

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 neuroprotective 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.

Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia

Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatment

Blood Glutamate Scavenging as a Novel Neuroprotective Treatment for Paraoxon Intoxication

Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure.

The neuroprotective effects of oxaloacetate and puruvate in a rat model of subarachnoid hemorrhage is mediated by its blood glutamate scavenging activity

Boyko, M.; Gruenbaum, S. E.; Gruenbaum, B. F.; Dubilet, M.; Zlotnik, A. Author Information

Blood Glutamate Scavenging: Insight into Neuroprotection

Brain insults are characterized by a multitude of complex processes, of which glutamate release plays a major role. Deleterious excess of glutamate in the brain’s extracellular fluids stimulates glutamate receptors, which in turn lead to cell swelling, apoptosis, and neuronal death. These exacerbate neurological outcome. Approaches aimed at antagonizing the astrocytic and glial glutamate receptors have failed to demonstrate clinical benefit. Alternatively, eliminating excess glutamate from brain interstitial fluids by making use of the naturally occurring brain-to-blood glutamate efflux has been shown to be effective in various animal studies. This is facilitated by gradient driven transport across brain capillary endothelial glutamate transporters. Blood glutamate scavengers enhance this naturally occurring mechanism by reducing the blood glutamate concentration, thus increasing the rate at which excess glutamate is cleared. Blood glutamate scavenging is achieved by several mechanisms including: catalyzation of the enzymatic process involved in glutamate metabolism, redistribution of glutamate into tissue, and acute stress response. Regardless of the mechanism involved, decreased blood glutamate concentration is associated with improved neurological outcome. This review focuses on the physiological, mechanistic and clinical roles of blood glutamate scavenging, particularly in the context of acute and chronic CNS injury. We discuss the details of brain-to-blood glutamate efflux, auto-regulation mechanisms of blood glutamate, natural and exogenous blood glutamate scavenging systems, and redistribution of glutamate. We then propose different applied methodologies to reduce blood and brain glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging.

914 Blood Glutamate Scavengers Prolong the Survival of Rats and Mice With Brain-implanted Gliomas

914 Blood Glutamate Scavengers Prolong the Survival of Rats and Mice With Brain-implanted Gliomas

The effect of blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome in a rat model of subarachnoid hemorrhage.

Blood glutamate scavengers have been shown to effectively reduce blood glutamate concentrations and improve neurological outcome after traumatic brain injury and stroke in rats. This study investigates the efficacy of blood glutamate scavengers oxaloacetate and pyruvate in the treatment of subarachnoid hemorrhage (SAH) in rats. Isotonic saline, 250mg/kg oxaloacetate, or 125mg/kg pyruvate was injected intravenously in 60 rats, 60 minutes after induction of SAH at a rate of 0.1ml/100g/min for 30 minutes. There were 20 additional rats that were used as a sham-operated group. Blood samples were collected at baseline and 90 minutes after SAH. Neurological performance was assessed at 24h after SAH. In half of the rats, glutamate concentrations in the cerebrospinal fluid were measured 24h after SAH. For the remaining half, the blood brain barrier permeability in the frontal and parieto-occipital lobes was measured 48h after SAH. Blood glutamate levels were reduced in rats treated with oxaloacetate or pyruvate at 90 minutes after SAH (p < 0.001). Cerebrospinal fluid glutamate was reduced in rats treated with pyruvate (p < 0.05). Neurological performance was significantly improved in rats treated with oxaloacetate (p < 0.05) or pyruvate (p < 0.01). The breakdown of the blood brain barrier was reduced in the frontal lobe in rats treated with pyruvate (p < 0.05) and in the parieto-occipital lobes in rats treated with either pyruvate (p < 0.01) or oxaloacetate (p < 0.01). This study demonstrates the effectiveness of blood glutamate scavengers oxaloacetate and pyruvate as a therapeutic neuroprotective strategy in a rat model of SAH.

Hypothermia-induced neuroprotection in rats: evidence of a blood glutamate scavenging mechanism

Hypothermia-induced neuroprotection in rats: evidence of a blood glutamate scavenging mechanism

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

L-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.

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

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.

Effect of Glutamate and Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome and Pathohistology of the Hippocampus after Traumatic Brain Injury in Rats

Decreasing blood glutamate concentrations after traumatic brain injury accelerates brain-to-blood glutamate efflux, leading to improved neurologic outcomes. The authors hypothesize that treatment with blood glutamate scavengers should reduce neuronal cell loss, whereas administration of glutamate should worsen outcomes. The authors performed histologic studies of neuronal survival in the rat hippocampus after traumatic brain injury and treatment with blood glutamate scavengers. Traumatic brain injury was induced on anesthetized male Sprague-Dawley rats by a standardized weight drop. Intravenous treatment groups included saline (control), oxaloacetate, pyruvate, and glutamate. Neurologic outcome was assessed using a Neurological Severity Score at 1 h, and 1, 2, 7, 14, 21, 28 days. Blood glutamate was determined at baseline and 90 min. Four weeks after traumatic brain injury, a histologic analysis of surviving neurons was performed. Oxaloacetate and pyruvate treatment groups demonstrated increased neuronal survival (oxaloacetate 2,200 ± 37, pyruvate 2,108 ± 137 vs. control 1,978 ± 46, P < 0.001, mean ± SD). Glutamate treatment revealed decreased neuronal survival (1,715 ± 48, P < 0.001). Treatment groups demonstrated favorable neurologic outcomes at 24 and 48 h (Neurological Severity Score at 24 and 48 h: 5.5 (1-8.25), 5 (1.75-7.25), P = 0.02 and 3(1-6.5), 4 (1.75-4.5), P = 0.027, median ± corresponding interquartile range). Blood glutamate concentrations were decreased in the oxaloacetate and pyruvate treatment groups. Administration of oxaloacetate and pyruvate was not shown to have any adverse effects. The authors demonstrate that the blood glutamate scavengers oxaloacetate and pyruvate provide neuroprotection after traumatic brain injury, expressed both by reduced neuronal loss in the hippocampus and improved neurologic outcomes. The findings of this study may bring about new therapeutic possibilities in a variety of clinical settings.

Pyruvate’s blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke

In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke.

Effects of blood glutamate scavenging on cortical evoked potentials.

It is well known that traumatic or ischemic brain injury is followed by acute excitotoxicity caused by the presence of abnormally high glutamate (Glu) in brain fluids. It has recently been demonstrated that excess Glu can be eliminated from brain into blood following the intravenous administration of oxaloacetate (OxAc), which, by scavenging blood Glu, induces an enhanced and neuroprotective brain-to-blood Glu efflux. In this study, we subjected rats to intravenous OxAc administration (i.v., 12.5, 25, and 50mg/kg, respectively), and studied its effects on somatosensory evoked cortical potentials (EPs). Against our expectation, the amplitudes of EPs did not decrease but increased in a dose- and time-dependent manner after OxAc administration. Similar effects were observed when blood Glu scavenging was enhanced by combining OxAc (12.5mg/kgbw) with recombinant glutamate-oxaloacetate transaminase (GOT, 0.14nmol/100g rat). On the basis of these results, we suggest that the changes of amplitudes of the EPs involve not only a glutamatergic but also the weakening of a GABAergic component. We cannot rule out the possibility that OxAc penetrates into the brain and improves mitochondrial functions.