The Glutamate-Glutamine Cycle in Epilepsy

Epilepsy is a complex, multifactorial disease characterized by spontaneous recurrent seizures and an increased incidence of comorbid conditions such as anxiety, depression, cognitive dysfunction, and sudden unexpected death. About 70 million people worldwide are estimated to suffer from epilepsy, and up to one-third of all people with epilepsy are expected to be refractory to current medications. Development of more effective and specific antiepileptic interventions is therefore requisite. Perturbations in the brain's glutamate-glutamine cycle, such as increased extracellular levels of glutamate, loss of astroglial glutamine synthetase, and changes in glutaminase and glutamate dehydrogenase, are frequently encountered in patients with epilepsy. Hence, manipulations of discrete glutamate-glutamine cycle components may represent novel approaches to treat the disease. The goal of his review is to discuss some of the glutamate-glutamine cycle components that are altered in epilepsy, particularly neurotransmitters and metabolites, enzymes, amino acid transporters, and glutamate receptors. We will also review approaches that potentially could be used in humans to target the glutamate-glutamine cycle. Examples of such approaches are treatment with glutamate receptor blockers, glutamate scavenging, dietary intervention, and hypothermia.