Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke.
ABSTRACT 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.
- SourceAvailable from: Nitsan Kozlovsky[Show abstract] [Hide abstract]
ABSTRACT: Poststroke depression (PSD) is the most frequent psychological sequela following stroke. While previous studies describe the impact of age on brain infarct volume, brain edema, and blood-brain barrier (BBB) breakdown following ischemia, the role of age on PSD has yet to be described. Here, we examine the influence of age on PSD progression in a rat model of PSD by middle cerebral artery occlusion (MCAO). One hundred forty-three rats were divided into three groups. 48 rats 20 weeks of age underwent a sham procedure, 51 rats 20 weeks of age had MCAO, and 44 rats 22-26 months of age had MCAO. Groups were further divided into two subgroups. The first subgroup was used to measure infarct lesion volume, brain edema, and BBB breakdown at 24 h. In the second subgroup at 3 weeks after MCAO, rats were subjected to a sucrose preference test, two-way shuttle avoidance task, forced swimming test, and a brain-derived neurotrophic factor (BDNF) protein level measurement. Total and striatal infarct volume, brain edema, and BBB breakdown in the striatum were increased in older rats, as compared with younger rats. While both old and young rats exhibited depressive-like behaviors on each of the behavioral tests and lower BDNF levels post-MCAO, as compared with control rats, there were no differences between old and young rats. Although older rats suffered from larger infarct volumes, increased brain edema and more BBB disruption following MCAO, the lack of behavioral differences between young and old rats suggests that there was no effect of rat age on the incidence of PSD.Cognitive Affective & Behavioral Neuroscience 06/2013; · 3.87 Impact Factor
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ABSTRACT: 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.Journal of Neural Transmission 03/2014; · 3.05 Impact Factor
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ABSTRACT: BACKGROUND:: The exact mechanism of hypothermia-induced neuroprotection has not been determined yet; however, we hypothesized that it may be mediated by a blood glutamate-scavenging effect. Here, we examine the effect of hypothermic conditions (mild, moderate, and deep) on blood glutamate levels in naive rats. To identify the mechanism of hypothermia-induced glutamate reduction, we also measured concentrations of glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT), the primary regulators of glutamate concentration in blood. METHODS:: Rats were anesthetized with isoflurane, and their rectal temperature was maintained for 6 hours at 36 to 37°C, 33 to 36°C, 30 to 32°C, 18 to 22°C, or was not maintained artificially. At 6 hours, active cooling was discontinued and rats were allowed to rewarm. There were 12 rats in each group for a total of 60 rats. Blood samples were drawn at 0, 3, 6, 12, 24, and 48 hours for the determination of blood glutamate, GOT, and GPT levels. RESULTS:: A strong correlation between body temperature and blood glutamate levels was observed (P<0.001). Mild (33 to 36°C) and moderate (30 to 32°C) hypothermia led to reduced blood glutamate levels (P<0.001). Deep hypothermia (18 to 22°C) was associated with significant elevations in blood glutamate levels (P<0.001). Hypothermia, irrespective of the degree, led to elevations in GOT in plasma (P<0.001). CONCLUSIONS:: Mild and moderate hypothermia led to a reduction in blood glutamate levels in rats, whereas deep hypothermia was associated with a significant elevation in blood glutamate levels. We further demonstrated an elevation of GOT and GPT levels, supporting their involvement in reducing blood glutamate by the conversion of glutamate to 2-ketoglutarate. We suggest that the neuroprotective properties of hypothermia may be partially because of a blood glutamate-scavenging mechanism.Journal of neurosurgical anesthesiology 01/2013; · 2.41 Impact Factor