Dr. Ron’s Research Review – April 27, 2016

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This week’s research review focuses on blood glutamate scavenging therapy by Vivian Teichberg.

Glutamate is the most important and abundant excitatory neurotransmitter. Glutamate also induces direct and potent effects on most if not all cells of the immune system. Due to these effects, it has been proposed to ‘upgrade’ Glutamate and recall it a ‘NeuroImmunotransmitter’ instead of a ‘Neurotransmitter.’ (Levite Teichberg and Riederer, 2014)
Elevated glutamate levels in the brain are associated with secondary brain injury following acute and chronic brain insults. The excess glutamate induces overstimulation of Glutamate receptors leading to neuro-degeneration and neuronal death through a process called ‘Excitotoxicity’.
Vivian Teichberg discovered he could inject into the blood a Glutamic Oxaloacetic Transaminase (GOT) enzyme, which would lower blood Glutamate levels, leading to a higher driving force for efflux (i.e. exit) of excess Glutamate from the brain to the blood.
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.  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. (Boyko et al., 2014)

SGOT: Serum glutamic oxaloacetic transaminase is a P5P-dependent enzyme.

Aspartate + α-ketoglutarate ↔ oxaloacetate + glutamate

Dr. Ron


 

Articles

Brain to blood glutamate scavenging as a novel therapeutic modality: a review.
            (Boyko et al., 2014) Download
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.

Blood glutamate scavenging: insight into neuroprotection.
            (Leibowitz et al., 2012) Download
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.

Glutamate and Vivian Teichberg: a story about science, medicine, memory and love.
            (Levite Teichberg and Riederer, 2014) Download
‘Brain to blood Glutamate scavenging’ is a novel therapeutic approach developed by Prof. Vivian Teichberg, Israel for preventing or minimizing the brain damage induced by excess Glutamate in many human diseases and injuries.

 

 

References

Boyko, M, et al. (2014), ‘Brain to blood glutamate scavenging as a novel therapeutic modality: a review.’, J Neural Transm (Vienna), 121 (8), 971-79. PubMed: 24623040
Leibowitz, A, et al. (2012), ‘Blood glutamate scavenging: insight into neuroprotection.’, Int J Mol Sci, 13 (8), 10041-66. PubMed: 22949847
Levite Teichberg, M and P Riederer (2014), ‘Glutamate and Vivian Teichberg: a story about science, medicine, memory and love.’, J Neural Transm (Vienna), 121 (8), 793-96. PubMed: 25081017