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

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 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.

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

“…Given the lack of spatial resolution, our current experiments make it difficult to interpret a role for GPT2 in the glutamate-glutamine cycle at the synapse. Indeed, the GPT enzyme has been used experimentally and in therapeutic models to reduce excitotoxic glutamate levels through a proposed scavenging approach (33). In the postnatal brain at P18, our experiments seem to indicate that Gpt2 serves to provide a source of alanine in the brain.…”

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

“…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.…”

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

“…This mechanism is based on the administration of oxaloacetate or recombinant glutamate oxaloacetate transaminase 1 (rGOT1), which leads to a metabolization and reduction of glutamate in blood and a subsequent lowering of glutamate in the cerebral parenchyma (see Campos et al 13 and Teichberg et al 14 for review). The protective efficacy of this strategy has been widely shown by independent laboratories in different types of ischemic animal models, [15][16][17][18][19][20] and it has also been tested in other pathologies associated with brain glutamate increase, such as traumatic brain injury, 21,22 subarachnoid hemorrhage, 23,24 or glioma, 25 with successful results. However, the use of blood glutamate grabbers has never been tested in an ICH model.…”