Roles of Glutamine Synthetase Inhibition in Epilepsy

Abstract

Glutamine synthetase (GS, E.C. 6.3.1.2) is a ubiquitous and highly compartmentalized enzyme that is critically involved in several metabolic pathways in the brain, including the glutamine-glutamate-GABA cycle and detoxification of ammonia. GS is normally localized to the cytoplasm of most astrocytes, with elevated concentrations of the enzyme being present in perivascular endfeet and in processes close to excitatory synapses. Interestingly, an increasing number of studies have indicated that the expression, distribution, or activity of brain GS is altered in several brain disorders, including Alzheimer’s disease, schizophrenia, depression, suicidality, and mesial temporal lobe epilepsy (MTLE). Although the metabolic and functional sequelae of brain GS perturbations are not fully understood, it is likely that a deficiency in brain GS will have a significant biological impact due to the critical metabolic role of the enzyme. Furthermore, it is possible that restoration of GS in astrocytes lacking the enzyme could constitute a novel and highly specific therapy for these disorders. The goals of this review are to summarize key features of mammalian GS under normal conditions, and discuss the consequences of GS deficiency in brain disorders, specifically MTLE.

Restoration Of Glutamine Synthetase Activity, Nitric Oxide Levels And Amelioration Of Oxidative Stress By Propolis In Kainic Acid Mediated Excitotoxicity

“…Neuronal excitation involving the excitatory glutamate receptors is recognized as an important underlying mechanism in neurodegenerative disorders (Wang et al 2005). Several studies have indicated that the activity of GS in astrocytes is diminished in several brain disorders, including epilepsy (Eid et al, 2012). Earlier studies have shown the decreased activity and expression of GS in kainic acid induced epilepsy and it has been hypothesized that the loss of GS activity in epilepsy leads to increased extracellular glutamate concentrations and epileptic seizures (Swamy et al, 2011a, b).…”

Cerebral Glucose Metabolism in an Immature Rat Model of Pediatric Traumatic Brain Injury

“…28,35 Thus, neurons are dependent on properly functioning astrocytes, and perturbations in astrocyte specific enzymes, including glutamine synthetase, have been described in many pathological conditions. [36][37][38] Glutamine synthetase is localized in astrocytic cytoplasm, and one of its main roles is to detoxify glutamate and ammonia by converting them into glutamine. The rate of glutamine synthesis can be directly determined by label incorporation into glutamine.…”

Glutamine and Epilepsy

“…Note the metabolic relationship among astrocytes, GABAergic neurons, and glutamatergic neurons as indicated by the glutamine-glutamate-GABA cycle ( purple arrows to the left ) and the glutamine-glutamate cycle ( red arrows to the right ). ADP adenosine diphosphate, ASAT aspartate aminotransferase, ATP adenosine triphosphate, GABA c-aminobutyric acid, coA coenzyme A, GAT3 GABA transporter subtype 3, GAD65 / 67 glutamate decarboxylase isoforms 65/67, GDH glutamate dehydrogenase, MCTs monocarboxylate transporters, PAG phosphate-activated glutaminase, SAT1 / 2 system A transporter subtypes 1/2, SN1 system N transporter subtype 1, VGAT vesicular GABA transporter, VGLUT vesicular glutamate transporter (Adapted from [ 36 ] and reproduced with permission from Neurochem Res\Springer) glutamate transporters (VGLUT) [ 13 , 14 ]. After release from synaptic vesicles, glutamate binds to glutamate receptors in neurons and glial cells.…”

“…The mechanism may be same as that in clinical seizures induced by fever in patients with febrile convulsions or epilepsy. The reason for the pronounced increase could result from the slow rates of glutamate-glutamine cycling, although the release of glutamate from astrocytes into extracellular space may also be involved [ 36 ]. By magnetic resonance spectroscopy, the epileptogenic, gliotic human hippocampus appears to be characterized metabolically by an increase in glutamate content, decreased glutamine content, and slow rates of glutamate-glutamine cycling [ 37 ].…”

“…It has been hypothesized that in glutamine-signifi cant depletion situations, the supplement of exogenous glutamine may assume a primary role in the support of excitatory neurotransmission, and inhibition of glutamine synthesis may further compromise the excitatory neurotransmitter synthesis [ 45 ]. However, in TLE patients, the loss of GS is spatially restricted to specifi c areas mostly CA1, CA3 and dentate hilus, which allows the supplement of glutamine from other non-compromised region, therefore the excitatory neurotransmitter synthesis may not be compromised and the accumulation of extracellular glutamate is reasonable [ 36 ].…”