https://orcid.org/0000-0002-5361-0414
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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.
Acknowledgements
TE was supported by grants from the National Institutes of Health (NIH; NS058674 and NS070824), Citizens United for Research in Epilepsy (CURE), and the Swebilius Family Trust. HZ was supported by grants from the National Science Foundation and the Swebilius Family Trust. The work was also made possible by a grant from the National Center for Advancing Translational Sciences (NCATS; UL1 TR000142), a component of the NIH and the NIH roadmap for Medical Research.
Disclosure statement
No potential conflict of interest was reported by the authors.
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Notes on contributors
Roni Dhaher
Roni Dhaher is a Associate research scientist, responsible for developing and carrying out experiments, analyzing data, and writing manuscript.
Eric C. Chen
Erin C. Chen is a Undergraduate student, responsible for carrying out experiments, analyzing data, and writing manuscript.
Edgar Perez
Edgar Perez is a Medical student, responsible for developing and carrying out experiments.
Amedeo Rapuano
Amadeo Rapuano is a Research Associate, responsible for carrying out histological analysis.
Mani Ratnesh S. Sandhu
Mani Ratnesh S. Sandhu is a Graduate Student and medical doctor, responsible for carrying out EEG analysis.
Shaun E. Gruenbaum
Shaun E. Gruenbaum is a Graduate Student and medical doctor, aided with carrying out research experiments.
Ketaki Deshpande
Ketaki Deshpande is a Post-doctoral associate, responsible for carrying out mass spectrometry and glutamine level analysis.
Feng Dai
Feng Dai is a Doctor of Philosophy, aided with statistical analysis.
Hitten P. Zaveri
Hitten P. Zaveri is a Assistant Professor, aiding with analysis of data and writing of manuscript.
Tore Eid
Tore Eid is a Associate Professor, responsible for developing experiments, analyzing data, and writing manuscript.