In recent years there has been a growing body of clinical and laboratory evidence demonstrating the neuroprotective effects of estrogen and progesterone after traumatic brain injury (TBI) and spinal cord injury (SCI). In humans, women have been shown to have a lower incidence of morbidity and mortality after TBI compared with age-matched men. Similarly, numerous laboratory studies have demonstrated that estrogen and progesterone administration is associated with a mortality reduction, improvement in neurological outcomes, and a reduction in neuronal apoptosis after TBI and SCI. Here, we review the evidence that supports hormone-related neuroprotection and discuss possible underlying mechanisms. Estrogen and progesterone-mediated neuroprotection are thought to be related to their effects on hormone receptors, signaling systems, direct antioxidant effects, effects on astrocytes and microglia, modulation of the inflammatory response, effects on cerebral blood flow and metabolism, and effects on mediating glutamate excitotoxicity. Future laboratory research is needed to better determine the mechanisms underlying the hormones’ neuroprotective effects, which will allow for more clinical studies. Furthermore, large randomized clinical control trials are needed to better assess their role in human neurodegenerative conditions.

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.

Background: 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. Methods: 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.

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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.

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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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