Metabolic aspects of epilepsy: prospects for metabolome research
https://doi.org/10.17650/2073-8803-2025-20-1-25-31
Abstract
Epilepsy is one of the most common neurological diseases. Despite the availability of modern antiepileptic drugs, up to 30 % of patients fail to achieve control over seizures and develop pharmacoresistancy, which leads to decrease in quality of life, social and professional limitations as well as their stigmatization in society. Epilepsy is closely connected with malfunction of one of the most metabolically active systems of our body – the central nervous system and seizures can be the cause of this metabolic failure as well as its consequence. Metabolomics is a new, rapidly developing scientific area and a promising tool for postgenomic research by studying biological fluids. The study of metabolome is the analysis of the combination of low molecular weight substances (metabolites) of an organism or biological sample, including various substances such as aminoacids, organic acids, sugars, steroids, nucleotides and lipids. This review summarizes the results of studies concerning the role of metabolic disorders in epileptogenesis. The analysis of scientific publications devoted to the assessment of the metabolic profile in epilepsy, the study of its features depending on the phenotype of the disease, and the response to therapy. Probably, further studies of metabolism will allow us to identify new biomarkers that can be used in the process of diagnostic search, in determining the prognosis of the disease and personification of therapy.
About the Authors
D. O. SigalovRussian Federation
Daniil O. Sigalov - Department of Nervous Diseases.
64 Vorovskogo St., Chelyabinsk 454141
M. I. Karpova
Russian Federation
Department of Nervous Diseases.
64 Vorovskogo St., Chelyabinsk 454141
A. F. Dolinina
Russian Federation
Department of Nervous Diseases, South Ural State Medical University; Chelyabinsk Regional Children’s Clinical Hospital.
64 Vorovskogo St., Chelyabinsk 454141; 42A Blukhera St., Chelyabinsk 454087
A. I. Sinitskii
Russian Federation
Department of Biochemistry named after R.I. Lifshitz.
64 Vorovskogo St., Chelyabinsk 454141, Russia
References
1. Alqurashi R.S., Yee A.S., Malone T. et al. A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis. PLoS One 2021;16(8):e0252282. DOI: 10.1371/journal.pone.0252282
2. Banerji R., Huynh C., Figueroa F. et al. Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome. Brain Commun 2021;3(1):fcab004. DOI: 10.1093/braincomms/fcab004
3. Belanger M., Allaman I., Magistretti P.J. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011;14(6):724–38. DOI: 10.1016/j.cmet.2011.08.016
4. Bogdanov M., Matson W.R., Wang L. et al. Metabolomic profiling to develop blood biomarkers for Parkinson’s disease. Brain 2008;131(Pt 2):389–96. DOI: 10.1093/brain/awm304
5. Boguszewicz Ł., Jamroz E., Ciszek M. et al. NMR-based metabolomics in pediatric drug resistant epilepsy – preliminary results. Sci Rep 2019;9(1):15035. DOI: 10.1038/s41598-019-51337-z
6. Boison D., Yegutkin G.G. Adenosine metabolism: Emerging concepts for cancer therapy. Cancer Cell 2019;36(6):582–96. DOI: 10.1016/j.ccell.2019.10.007
7. Choi J., Nordli Jr D.R., Alden T.D. et al. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation 2009;6:38. DOI: 10.1186/1742-2094-6-38
8. Dalic L., Cook M.J. Managing drug-resistant epilepsy: Challenges and solutions. Neuropsychiatr Dis Treat 2016;12:2605–16. DOI: 10.2147/NDT.S84852
9. Dienel G.A. Brain glucose metabolism: Integration of energetics with function. Physiol Rev 2019;99:949–1045. DOI: 10.1152/physrev.00062.2017
10. Ethemoglu O., Ay H., Koyuncu I. et al. Comparison of cytokines and prooxidants/antioxidants markers among adults with refractory versus well-controlled epilepsy: A cross-sectional study. Seizure 2018;60:105–9. DOI: 10.1016/j.seizure.2018.06.009
11. Fisher R.S., Acevedo C., Arzimanoglou A. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–82. DOI: 10.1111/epi.12550
12. Godoi A.B., do Canto A.M., Donatti A. et al. Circulating metabolites as biomarkers of disease in patients with mesial temporal lobe epilepsy. Metabolites 2022;12(5):446. DOI: 10.3390/metabo12050446
13. Govil-Dalela T., Kumar A., Behen M.E. et al. Evolution of lobar abnormalities of cerebral glucose metabolism in 41 children with drug-resistant epilepsy. Epilepsia 2018;59(7):1307–15. DOI: 10.1111/epi.14404
14. Guo H.L., Wang W.J., Dong N. et al. Integrating metabolomics and lipidomics revealed a decrease in plasma fatty acids but an increase in triglycerides in children with drug-refractory epilepsy. Epilepsia Open 2023;8(2):466–78. DOI: 10.1002/epi4.12712
15. Güvenç C., Dupont P., den Stock J.V. et al. Correlation of neuropsychological and metabolic changes after epilepsy surgery in patients with left mesial temporal lobe epilepsy with hippocampal sclerosis. EJNMMI Res 2018;8(1):31. DOI: 10.1186/s13550-018-0385-5
16. Hall C.N., Klein-Flugge M.C., Howarth C. et al. Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing. J Neurosci 2012;32:8940–51. DOI: 10.1523/JNEUROSCI.0026-12.2012
17. Hasegawa T., Sumita M., Horitani Y. et al. Gas chromatography-mass spectrometry-based metabolic profiling of cerebrospinal fluid from epileptic dogs. J Vet Med Sci 2014;76(4):517–22. DOI: 10.1292/jvms.13-0520
18. Hassan-Smith G., Wallace G.R., Douglas M.R. et al. The role of metabolomics in neurological disease. J Neuroimmunol 2012;248(1–2):48–52. DOI: 10.1016/j.jneuroim.2012.01.009
19. Heischmann S., Quinn K., Cruickshank-Quinn C. et al. Exploratory metabolomics profiling in the kainic acid rat model reveals depletion of 25-hydroxyvitamin D3 during epileptogenesis. Sci Rep 2016;6:31424. DOI: 10.1038/srep31424
20. Hauser W.A., Beghi E. First seizure definitions and worldwide incidence and mortality. Epilepsia 2008;49(Suppl 1):8–12. DOI: 10.1111/j.1528-1167.2008.01443.x
21. Kaddurah-Daouk R., Kristal B.S., Weinshilboum R.M. Metabolomics: A global biochemical approach to drug response and disease. Annu Rev Pharmacol Toxicol 2008;48:653–83. DOI: 10.1146/annurev.pharmtox.48.113006.094715
22. Lovatt D., Sonnewald U., Waagepetersen H.S. et al. The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci 2007;27(45):12255–66. DOI: 10.1523/JNEUROSCI.3404-07.2007
23. Machler P., Wyss M.T., Elsayed M. et al. In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab 2016;23(1):94–102. DOI: 10.1016/j.cmet.2015.10.010
24. Magistretti P.J., Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 2018;19(4):235–49. DOI: 10.1038/nrn.2018.19
25. Murgia F., Muroni A., Puligheddu M. et al. Metabolomics as a tool for the characterization of drug-resistant epilepsy. Front Neurol 2017;8:459. DOI: 10.3389/fneur.2017.00459
26. Pan J.W., Williamson A., Cavus I. et al. Neurometabolism in human epilepsy. Epilepsia 2008;49(Suppl 3):31–41. DOI: 10.1111/j.1528-1167.2008.01508.x
27. Papadopoulou M.T., Muccioli L., Bisulli F. et al. Accessibility, availability and common practices regarding genetic testing for epilepsy across Europe: A survey of the European Reference Network EpiCARE. Epilepsia Open 2024;9(3):996–1006. DOI: 10.1002/epi4.12930
28. Patti G., Yanes O., Siuzdak G. Innovation: Metabolomics – the apogee of the omic trilogy. Nat Rev Mol Cell Biol 2012;13(4):263–9. DOI: 10.1038/nrm3314
29. Pellerin L., Magistretti P.J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 1994;91(22):10625–9. DOI: 10.1073/pnas.91.22.10625
30. Sada N., Lee S., Katsu T. et al. Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 2015;347(6228):1362–7. DOI: 10.1126/science.aaa1299
31. Saleem T.H., Nassar A.Y., El-Tallawy H.N. et al. Role of plasma amino acids profiles in pathogenesis and prediction of severity in patients with drug resistant epilepsy. Egypt J Hosp Med 2019;77(1):4681–7. DOI: 10.21608/ejhm.2019.45934
32. Smeland O.B., Hadera M.G., McDonald T.S. et al. Brain mitochondrial metabolic dysfunction and glutamate level reduction in the pilocarpine model of temporal lobe epilepsy in mice. J Cereb Blood Flow Metab 2013;33:1090–7. DOI: 10.1038/jcbfm.2013.54
33. Sokoloff L., Reivich M., Kennedy C. et al. The [14C] deoxyglucose method for the Measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977;28(5):897–916. DOI: 10.1111/j.1471-4159.1977.tb10649.x
34. Sokolova T.V., Zabrodskaya Y.M., Litovchenko A.V. et al. Relationship between neuroglial apoptosis and neuroinflammation in the epileptic focus of the brain and in the blood of patients with drug-resistant epilepsy. Int J Mol Sci 2022;23(20):12561. DOI: 10.3390/ijms232012561
35. Williams R.J. Biochemical Individuality, The Basis for the Genetotrophic Concept. Austin: University of Texas Press, 1956. 214 p.
36. Zhu Y., Feng J., Wu S. et al. Glucose metabolic profile by visual assessment combined with statistical parametric mapping analysis in pediatric patients with epilepsy. J Nucl Med 2017;58(8):1293–9. DOI: 10.2967/jnumed.116.187492
Review
For citations:
Sigalov D.O., Karpova M.I., Dolinina A.F., Sinitskii A.I. Metabolic aspects of epilepsy: prospects for metabolome research. Russian Journal of Child Neurology. 2025;20(1):25-31. (In Russ.) https://doi.org/10.17650/2073-8803-2025-20-1-25-31