Blood glutamate scavenging: Insight into neuroprotection

Several acute brain insults such as stroke, traumatic brain injury, meningitis, subarachnoid hemorrhage, and chronic neurodegenerative states such as Alzheimer's disease and amyotrophic lateral sclerosis , are characterized by a deleterious excess of glutamate in brain's extracellular fluids. Excess of glutamate in brain interstitium, facilitates stimulation of glutamate receptors, which in turn lead to cell swelling, apoptosis and neuronal death, thus exacerbating neurological outcome. The classic approach, was aimed at antagonizing the astrocytic and glial glutamate receptors. While being a potentially promising in animal models, this approach has failed to demonstrate sound clinical benefit. An alternative approach to eliminating excess glutamate from brains interstitial fluids and CSF has been proposed, derived from the discovery of brain capillary endothelial glutamate transporters. A naturally-occurring brain-to blood glutamate efflux facilitated by a gradient driven transport across these transporters, has been shown to eliminate excess glutamate from brain fluids. Blood glutamate scavengers enhance this naturally occurring mechanism, increasing the rate at which excess glutamate is cleared. Reduction of blood glutamate concentration in plasma establishes a new, more favorable concentration gradient, facilitating transport of excess glutamate from brains' extracellular fluids into the blood. Numerous studies demonstrate a strong correlation between blood glutamate concentrations and the concentration in the brain's extracellular fluid, thus suggesting that blood glutamate concentration might significantly affect glutamate concentration in brain. Recent studies have validated the effectiveness of the glutamate-scavenging approach in treatment of acute brain insults. Lower blood glutamate concentrations have been associated with improved neurological outcomes in both animal models and human studies. Conversely, elevated blood glutamate levels were associated with worse neurological outcomes. These findings lead to the notion that reducing elevated blood glutamate levels may play an important role in neuroprotection. One of the proposed blood glutamate reduction mechanisms introduced initially, involved the metabolism of glutamate into α-ketoglutarate. This naturally occurring enzymatic process is mediated by activation of resident plasma enzymes glutamateoxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) in the presence of their respective co-enzymes oxaloacetate and pyruvate. Further studies, based on blood glutamate reducing modalities other than oxaloacetate and pyruvate, have shown that additional mechanisms may be involved as well. These mechanisms share common physiological processes regulating blood glutamate levels. Acute stress response mediated via activation of β₂ adrenergic receptors, female gonadal hormones estrogen and progesterone, insulin, glucagon, elevated glucose levels and inter-compartmental redistribution - have all been shown to effectively reduce blood glutamate levels. Decreased blood glutamate concentration was associated with improved neurological outcome irrespective of the precise process which was involved in reducing glutamate concentration. Thus, the evolving role of blood glutamate levels in maintaining CNS glutamate homeostasis highlights the need to further characterize mechanisms involved in reducing blood glutamate. Keeping in mind the clinical applications of such modalities - these investigations should strive to identify those mechanisms which are least associated with adverse and toxic effects. To date, the promising results achieved with blood glutamate scavengers in animal models of brain insults, and the safety profile associated with these substances, warrants further studies in this field. This chapter concentrates on the physiologic, 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, autoregulation 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's glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging.