Roni Dhaher1, Eric C Chen2, Edgar Perez2, Amedeo Rapuano1, Mani Ratnesh S Sandhu2, Shaun E Gruenbaum3, Ketaki Deshpande2, Feng Dai4, Hitten P Zaveri5, Tore Eid2. 1. Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. 2. Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA. 3. Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA. 4. Department of Biostatistics, Yale School of Medicine, New Haven, CT, USA. 5. Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Abstract
Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease. Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n = 8) or pure water (n = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures. Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition. Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.
Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease. Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n = 8) or pure water (n = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures. Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition. Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.
Authors: Puneet Bagga; Kevin L Behar; Graeme F Mason; Henk M De Feyter; Douglas L Rothman; Anant B Patel Journal: J Cereb Blood Flow Metab Date: 2014-07-30 Impact factor: 6.200
Authors: Christine A Olson; Helen E Vuong; Jessica M Yano; Qingxing Y Liang; David J Nusbaum; Elaine Y Hsiao Journal: Cell Date: 2018-05-24 Impact factor: 41.582