Inducible Glutamate Oxaloacetate Transaminase as a Therapeutic Target Against Ischemic Stroke

Abstract

Significance: Glutamate serves multi-faceted (patho)physiological functions in the central nervous system as the most abundant excitatory neurotransmitter and under pathological conditions as a potent neurotoxin. Regarding the latter, elevated extracellular glutamate is known to play a central role in ischemic stroke brain injury. Recent Advances: Glutamate oxaloacetate transaminase (GOT) has emerged as a new therapeutic target in protecting against ischemic stroke injury. Oxygen-sensitive induction of GOT expression and activity during ischemic stroke lowers glutamate levels at the stroke site while sustaining adenosine triphosphate levels in brain. The energy demands of the brain are among the highest of all organs underscoring the need to quickly mobilize alternative carbon skeletons for metabolism in the absence of glucose during ischemic stroke. Recent work builds on the important observation of Hans Krebs that GOT-mediated metabolism of glutamate generates tri-carboxylic acid (TCA) cycle intermediates in brain tissue. Taken together, outcomes suggest GOT may enable the transformative switch of otherwise excitotoxic glutamate into life-sustaining TCA cycle intermediates during ischemic stroke. Critical Issues: Neuroprotective strategies that focus solely on blocking mechanisms of glutamatemediated excitotoxicity have historically failed in clinical trials. That GOT can enable glutamate to assume the role of a survival factor represents a paradigm shift necessary to develop the overall significance of glutamate in stroke biology. Future Directions: Ongoing efforts are focused to develop the therapeutic significance of GOT in stroke-affected brain. Small molecules that target induction of GOT expression and activity in the ischemic penumbra are the focus of ongoing studies. Antioxid. Redox Signal. 22, 175-186.Neurotransmitter Glutamate I n modern neuroscience, glutamate is best known as the principle excitatory neurotransmitter of the mammalian central nervous system. The seminal observation published in 1954 by Hayashi that intracranial and endovascular delivery of glutamate produced seizures (36) sparked an entire field of research on excitatory amino acids and their receptors. Pioneering work from the late 1950's through the 1980's further characterized glutamatergic synaptic transmission (22,29,62) and led to identification of ionotropic (37) and metabotropic (58, 85) receptors, and mechanisms of glutamate uptake (6, 57) and transport (11, 94). As the neurotransmitter role of glutamate was discovered on the basis of pathological seizure activity (36), it is perhaps not surprising that research efforts since have continued to characterize the patho-physiological significance of neurotransmitter glutamate in neurologic disease. In 1957, the first neurotoxic effects of glutamate were described in mouse retina (52). Today, glutamate-mediated neurotoxicity has been implicated in a number of diseases affecting the central nervous system, including epilepsy, Parkinson's disease, multiple sclerosis, and t...

Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke‐affected brain

“…Glutamate is positioned to serve as an ideal metabolic substitute given its sequestration in neurons and the need to mitigate neurotoxic accumulation under pathophysiological conditions such as ischemic stroke. As a transaminase, GOT catalyzes the transfer of the amino group from glutamate to the 4‐carbon TCA cycle intermediate oxaloacetate to generate aspartate and the 5‐carbon TCA cycle intermediate α‐ketoglutarate (2). This ability enables the anaplerotic flux of GOT‐metabolized glutamate into a truncated TCA cycle.…”

“…Krebs observed that glutamate was the only amino acid that increased cellular respiration in the cortex of rabbit brain under hypoglycemic conditions (5). Given the pathophysiological role of glutamate‐mediated neurotoxicity and cell death in ischemic stroke injury (7) and in light of our observation that SO‐mediated induction of GOT protects against ischemic stroke injury (2–4), we hypothesize that GOT can utilize otherwise neurotoxic glutamate to support cell survival in the face of ischemia‐induced hypoglycemia. The current study is designed to test the significance of GOT‐mediated glutamate metabolism in neural cell culture and the hypoglycemic stroke‐affected brain.…”

“…Glutamatergic neurons rely on the liberal production of ATP from glucose via tricarboxylic acid cycle (TCA) in order to maintain energy‐expensive ion pumps that regulate neuro‐transmitter release and uptake (1). To that end, the disruption of glucose supply due to ischemic stroke incurs a rapid neurotoxic release of excitatory neurotransmitter glutamate at the synapse that contributes to neural cell death (2).…”

“…We have previously reported that correction of hypoxia by supplemental oxygen (SO) therapy during cerebral ischemia induces expression of the glutamate‐metabolizing enzyme glutamate oxaloacetate transaminase (GOT) and rescues brain tissue from stroke‐induced injury (2–4). GOT‐mediated metabolism of glutamate in brain tissue was first characterized by Krebs in 1935 (5).…”

Interaction of Excitatory Amino Acid Transporters 1 – 3 (EAAT1, EAAT2, EAAT3) with N-Carbamoylglutamate and N-Acetylglutamate

“…Oxaloacetate was recently introduced as a neuroprotective drug [19-22] due to ability to decrease blood glutamate levels by the activation of the blood-resident enzyme glutamate-oxaloacetate transaminase (GOT). This enzyme catalyzes, by transfer of an amino group, the transformation of glutamate into α-ketoglutarate and of oxaloacetate into L-aspartate.…”