5-aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy
Open accessAbstract
Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant, localization-related epilepsies in humans. One potential therapeutic target is the brain glutamine-glutamate-GABA metabolic pathway, which is perturbed in patients with MTLE. Loss of glutamine synthetase (GS) in astrocytes may be critically involved in this perturbation, which can be modeled by infusing the GS inhibitor methionine sulfoximine (MSO) into the entorhinal-hippocampal area in rats. Because 5-aminovaleric acid (5-AV) has been implicated in modulation of the glutamine-glutamate-GABA metabolic pathway, we hypothesized that 5-AV would alter the expression of seizures in the MSO model of MTLE. Male Sprague Dawley rats (300-330g) were implanted with an Alzet pump placed subcutaneously in the abdominal region to release either 5-AV (0.05mg/mL, n=6) or phosphate buffered saline (PBS, n=6) at a rate of 2.5μl/h over 28days. Five to 7days after surgery, all rats were implanted with an intracranial pump infusing MSO (2.5mg/mL; 0.25μl/h) unilaterally into the hippocampal formation. Following the second surgery, intracranial EEG was measured from the left and right hemispheres above the dorsal hippocampal formations for a continuous period of 21days. The EEG was correlated with simultaneous video recordings to determine the stage of seizures according to a modified Racine scale. Five-AV-treated rats experienced a 3.5 fold reduction in the number of seizures (6.7±1.4seizures/day) than PBS-treated rats (23.2±6.3seizures/day) during the first 2days following MSO pump placement (p<0.005). Both groups showed similar seizure frequency over days 3-21 (~1seizure/day). However, the fraction of the most severe type of seizures (Racine stages 4 and 5) increased over time in the PBS treated group, but not in the 5-AV treated group. Notably, 5-AV treated rats experienced a 2.3 and 2.6 fold lower fraction of stage 4 and 5 seizures than PBS-treated rats during the 2nd and 3rd weeks of MSO treatment respectively (p<0 .05 and p<0.001 respective to week). Five-AV markedly reduces the number of seizures initially and suppresses the development of the most severe type of seizures in the MSO model of MTLE. These results may have implications for the therapeutic use of 5-AV in treating mesial temporal lobe seizures and for our understanding of the chemical pathology of epileptogenesis and MTLE.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
5AV acts as an anticonvulsant in mice.
“5AV acts as an anticonvulsant in mice (Dhaher et al., 2014; Samuels et al., 1983).”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Dhaher et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Danbolt, N. C. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00067-8 · Cited by 4,068 · see citing works
Glutamine Synthetase: Glial Localization in Brain
Martinez-Hernandez, A., Bell, K. P., & Norenberg, M. D. (1977) · Science · doi:10.1126/science.14400 · Cited by 1,183 · see citing works
On the Origin of Interictal Activity in Human Temporal Lobe Epilepsy in Vitro
Cohen, I., Navarro, V., Clémenceau, S., Baulac, M., & Miles, R. (2002) · Science · doi:10.1126/science.1076510 · Cited by 1,001 · see citing works
Prevalence of Epilepsy in Rochester, Minnesota: 1940–1980
Hauser, W. A., Annegers, J. F., & Kurland, L. T. (1991) · Epilepsia · doi:10.1111/j.1528-1157.1991.tb04675.x · Cited by 848 · see citing works
Clinical and Electroencephalographical Classification of Epileptic Seizures
Gastaut, H. (1970) · Epilepsia · doi:10.1111/j.1528-1157.1970.tb03871.x · Cited by 559 · see citing works
Eid, T., Thomas, M., Dd, S., Rundén‐Pran, E., Lai, J. C. K., Malthankar, G. V., Kim, J., Danbolt, N. C., Ottersen, O. P., & de Lanerolle, N. C. (2004) · The Lancet · doi:10.1016/s0140-6736(03)15166-5 · Cited by 434 · see citing works
Self-citationEpileptic seizures and syndromes
Niedermeyer, E. (1995) · Electroencephalography and Clinical Neurophysiology · doi:10.1016/0013-4694(95)90533-2 · Cited by 332 · see citing works
Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome
Albrecht, J., & Jones, E. A. (1999) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(99)00169-0 · Cited by 280 · see citing works
Causes of Epilepsy: Contributions of the Rochester Epidemiology Project
Annegers, J. F., Rocca, W. A., & Hauser, W. A. (1996) · Mayo Clinic Proceedings · doi:10.4065/71.6.570 · Cited by 233 · see citing works
Glutamate–glutamine Cycling in the Epileptic Human Hippocampus
Petroff, O. A. C., Errante, L. D., Rothman, D. L., Kim, J., & Spencer, D. D. (2002) · Epilepsia · doi:10.1046/j.1528-1157.2002.38901.x · Cited by 206 · see citing works
Racine, R. J., Burnham, W. M., Gartner, J. G., et al. (1973) · Electroencephalography and Clinical Neurophysiology · doi:10.1016/0013-4694(73)90033-3 · Cited by 181 · see citing works
Anion Currents and Predicted Glutamate Flux through a Neuronal Glutamate Transporter
Otis, T. S., & Jahr, C. E. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07099.1998 · Cited by 179 · see citing works
Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy
van der Hel, W. S., Notenboom, R. G. E., Bos, I. W. M., van Rijen, P. C., Veelen, C. W. M. V., & Graan, P. N. E. D. (2005) · Neurology · doi:10.1212/01.wnl.0000149636.44660.99 · Cited by 166 · see citing works
Muhyaddin, M. S., ROBERTS, P. J., & Woodruff, G. N. (1982) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1982.tb09282.x · Cited by 122 · see citing works
Bertram, E. H., Williamson, J. M., Cornett, J. F., et al. (1997) · Brain Research Protocols · doi:10.1016/s1385-299x(97)00033-0 · Cited by 81 · see citing works
Nanavati, S. M., & Silverman, R. B. (1989) · Journal of Medicinal Chemistry · doi:10.1021/jm00131a001 · Cited by 76 · see citing works
Wang, Y., Zaveri, H. P., Lee, T.-S. W., & Eid, T. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.08.034 · Cited by 50 · see citing works
Self-citationBaclofen, gamma-aminobutyric acidB receptors and substance P in the mouse spinal cord.
Hwang, A. S., & Wilcox, G. L. (1989) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24118-0 · Cited by 50 · see citing works
The Time Course and Circuit Mechanisms of Acquired Epileptogenesis
Dudek, F. E., & Staley, K. J. (2012) · Oxford University Press eBooks · doi:10.1093/med/9780199746545.003.0031 · Cited by 49 · see citing works
Effects of the putative antagonists phaclofen and δ‐aminovaleric acid on GABAB receptor biochemistry
Robinson, T. N., Cross, A. J., Green, A. R., et al. (1989) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1989.tb14612.x · Cited by 40 · see citing works
On the mechanism of anticonvulsant effect of tramadol in mice
Manocha, A., Sharma, K. K., & Mediratta, P. K. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.07.013 · Cited by 36 · see citing works
Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice
Manocha, A. (2003) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(03)00218-1 · Cited by 35 · see citing works
Possible mechanism of anticonvulsant effect of ketamine in mice.
Manocha, A., Sharma, K. K., & Mediratta, P. K. (2001) · PubMed · Cited by 31 · see citing works
Baclofen activates two distinct receptors in the rat spinal cord and guinea pig ileum
Sawynok, J. (1986) · Neuropharmacology · doi:10.1016/0028-3908(86)90098-5 · Cited by 27 · see citing works
Stirling, J. M., Cross, A. J., Robinson, T. N., et al. (1989) · Neuropharmacology · doi:10.1016/0028-3908(89)90153-6 · Cited by 25 · see citing works
The Ligand-induced Structural Changes of Humanl-Arginine:Glycine Amidinotransferase
Fritsche, E., Humm, A., & Huber, R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.5.3026 · Cited by 23 · see citing works
Santicioli, P., Maggi, C. A., & Meli, A. (1986) · Journal of Autonomic Pharmacology · doi:10.1111/j.1474-8673.1986.tb00631.x · Cited by 20 · see citing works
Allan, R. D., & Dickenson, H. W. (1986) · European Journal of Pharmacology · doi:10.1016/0014-2999(86)90650-3 · Cited by 20 · see citing works
Kindling, Spontaneous Seizures, and the Consequences of Epilepsy: More Than a Model
Sutula, T. P., & Ockuly, J. C. (2006) · Elsevier eBooks · doi:10.1016/b978-012088554-1/50034-7 · Cited by 17 · see citing works
Interictal discharges in the hippocampus of rats with long-term pilocarpine seizures
Nagao, T., Avoli, M., & GLOOR, P. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90011-6 · Cited by 16 · see citing works
Samuels, S., Fish, I., & Schwartz, S. A. (1983) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1983.tb08093.x · Cited by 14 · see citing works
Holopainen, I. E., Rau, C., & Wojcik, W. J. (1992) · European Journal of Pharmacology Molecular Pharmacology · doi:10.1016/0922-4106(92)90132-f · Cited by 11 · see citing works
Glial uptake system of GABA distinct from that of taurine in the bullfrog sympathetic ganglia
Tasaka, J., Sakai, S., Tosaka, T., & Yoshihama, I. (1989) · Neurochemical Research · doi:10.1007/bf00971323 · Cited by 9 · see citing works
Possible mechanism involved in the anticonvulsant action of butorphanol in mice
Manocha, A., Sharma, K. K., & Mediratta, P. K. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(02)01004-3 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Sharon, G., Cruz, N. J., Kang, D.-W., Gandal, M. J., Wang, B., Kim, Y.-M., Zink, E. M., Casey, C. P., Taylor, B. C., Lane, C. J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.004 · Cited by 1,182 · see citing works
Gut microbiome and depression: what we know and what we need to know
Winter, G., Hart, R. A., Charlesworth, R. P. G., & Sharpley, C. F. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0072 · Cited by 394 · see citing works
- Authors
- Dhaher, R., Damisah, E. C., Wang, H., Gruenbaum, S. E., Ong, C., Zaveri, H. P., Gruenbaum, B. F., & Eid, T.
- Affiliations
- Yale University (US)
- Corresponding author
- Eid, Tore
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 67
- Pages
- 18-23
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4035438
- OpenAlex
- W2099939080
- Cited by
- 20
- References
- 34
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 3 · 2022: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 1
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (NS058674, NS070824)
- National Center for Advancing Translational Sciences (NCATS) (UL1 RR024139)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- 5-aminovaleric acid, mesial temporal lobe epilepsy, methionine sulfoximine, glutamine synthetase inhibition, astrocytes, seizure severity, Racine scale, hippocampus, entorhinal cortex, antiepileptic drugs, intracerebroventricular infusion, intracranial EEG, drug-resistant epilepsy
- MeSH terms
- Animals, Brain, Disease Models, Animal, Epilepsy, Temporal Lobe, Male, Methionine Sulfoximine, Seizures, Rats, Sprague-Dawley, Amino Acids, Neutral, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
