{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T07:27:35Z","timestamp":1772609255511,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004801","name":"Shota Rustaveli National Science Foundation","doi-asserted-by":"crossref","award":["FR-21-5004"],"award-info":[{"award-number":["FR-21-5004"]}],"id":[{"id":"10.13039\/501100004801","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["2021-03209"],"award-info":[{"award-number":["2021-03209"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epilepsy is a prevalent neurological disorder characterized by spontaneous recurrent seizures (SRS). Epileptogenesis is a multifaceted pathophysiological process that transforms a normal brain into one prone to chronic seizures. Targeting epileptogenesis is a compelling line of epilepsy therapy. Thus, discovering new drugs that oppose, mitigate, or modify epileptogenesis is a significant challenge in modern neuroscience. Our previous work demonstrated that, in a kainic acid (KA)-induced post-status epilepticus model, 28 days myo-inositol (MI) treatment reduces frequency and duration of motor and electrographic SRS even following cessation of treatment, for the following 4 weeks and identified MI as a promising antiepileptogenic compound To further evaluate the dose-dependent efficacy of MI, we applied the same experimental model using 30 mg\/kg (dose used in earlier studies), 60 mg\/kg, and 120 mg\/kg to assess effects on hippocampal electrographic and motor SRS, as well as KA-induced spatial learning and memory impairment in a Morris water maze test. We found that MI had long-lasting, dose-dependent suppressive effects on behavioral and electrographic manifestations of epileptogenesis and ameliorated spatial learning and memory deficit induced by SE, with 60 mg\/kg emerging as the most effective dose. Furthermore, we investigated transcriptomic and epigenetic alterations associated with the optimal MI dose and identified multiple affected pathways in the hippocampus. Interestingly, MI treatment resulted in transcriptomic upregulation and prevention of downregulation of several ion channel subunits, including GRIK3 and GRIN3A (kainate and NMDA receptor subunits) and the sodium channel subunit SCNB4. The obtained data highlight new molecular targets for epilepsy therapy and support the translational potential of MI.<\/jats:p>","DOI":"10.3390\/ijms262211102","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T10:24:58Z","timestamp":1763375098000},"page":"11102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dose-Dependent Effects of Myo-Inositol on Kainic Acid-Induced Epilepsy: Electrophysiological, Behavioral, Transcriptomic, and DNA Methylome Studies"],"prefix":"10.3390","volume":"26","author":[{"given":"Luka","family":"Kharkhelauri","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0965-0363","authenticated-orcid":false,"given":"Georgi","family":"Gamkrelidze","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veriko","family":"Bokuchava","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5545-8009","authenticated-orcid":false,"given":"Lia","family":"Tsverava","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"},{"name":"Iv. Beritashvili Centre of Experimental Biomedicine, 0160 Tbilisi, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eka","family":"Lepsveridze","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6552-6076","authenticated-orcid":false,"given":"Vincenzo","family":"Lagani","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"},{"name":"Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7984-3921","authenticated-orcid":false,"given":"Merab","family":"Kokaia","sequence":"additional","affiliation":[{"name":"Epilepsy Centre, Department of Clinical Sciences, Lund University Hospital, SE-221 00 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Revaz","family":"Solomonia","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, Ilia State University, 0162 Tbilisi, Georgia"},{"name":"Iv. Beritashvili Centre of Experimental Biomedicine, 0160 Tbilisi, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1146\/annurev.physiol.63.1.815","article-title":"On the Cellular and Network Bases of Epileptic Seizures","volume":"63","author":"McCormick","year":"2001","journal-title":"Annu. Rev. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1528-1167.2010.02602.x","article-title":"Therapeutic Approaches to Epileptogenesis\u2014Hope on the Horizon","volume":"51","author":"Pitkanen","year":"2010","journal-title":"Epilepsia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a022822","DOI":"10.1101\/cshperspect.a022822","article-title":"Epileptogenesis","volume":"5","author":"Lukasiuk","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lignani, G., Baldelli, P., and Marra, V. (2020). Homeostatic Plasticity in Epilepsy. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00197"},{"key":"ref_5","unstructured":"Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., and Delgado-Escueta, A.V. (2012). The Time Course and Circuit Mechanisms of Acquired Epileptogenesis, National Center for Biotechnology Information."},{"key":"ref_6","first-page":"185","article-title":"Purification and Identification of Components of the Aquilegia Vulgaris Extract Fraction Exhibiting Anti-Epileptic Activity","volume":"4","author":"Solomonia","year":"2004","journal-title":"J. Biol. Phys. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s10517-007-0016-z","article-title":"Effect of Myo-Inositol on Convulsions Induced by Pentylenetetrazole and Kainic Acid in Rats","volume":"143","author":"Solomonia","year":"2007","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s10571-012-9877-4","article-title":"Myo-Inositol Treatment and GABA-A Receptor Subunit Changes after Kainate-Induced Status Epilepticus","volume":"33","author":"Solomonia","year":"2013","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.neulet.2009.11.012","article-title":"Myo-Inositol Treatment Prevents Biochemical Changes Triggered by Kainate-Induced Status Epilepticus","volume":"468","author":"Solomonia","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kandashvili, M., Gamkrelidze, G., Tsverava, L., Lordkipanidze, T., Lepsveridze, E., Lagani, V., Burjanadze, M., Dashniani, M., Kokaia, M., and Solomonia, R. (2022). Myo-Inositol Limits Kainic Acid-Induced Epileptogenesis in Rats. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031198"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tsverava, L., Kandashvili, M., Margvelani, G., Lortkipanidze, T., Gamkrelidze, G., Lepsveridze, E., Kokaia, M., and Solomonia, R. (2019). Long-Term Effects of Myoinositol on Behavioural Seizures and Biochemical Changes Evoked by Kainic Acid Induced Epileptogenesis. Biomed Res. Int., 2019.","DOI":"10.1155\/2019\/4518160"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1097\/WNR.0000000000001341","article-title":"Concentration- and Time-Dependent Effects of Myo-Inositol on Evoked Epileptic Afterdischarge in the Hippocampus In Vivo","volume":"30","author":"Gamkrelidze","year":"2019","journal-title":"Neuroreport"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1046\/j.1471-4159.2002.01041.x","article-title":"Inositol and Higher Inositol Phosphates in Neural Tissues: Homeostasis, Metabolism and Functional Significance","volume":"82","author":"Fisher","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0006-8993(95)00395-7","article-title":"Modulation by Inositol of Cholinergic- and Serotonergic-Induced Seizures in Lithium-Treated Rats","volume":"685","author":"Williams","year":"1995","journal-title":"Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/epi4.13061","article-title":"Preventing Epileptogenesis by Interaction between Inositol Isomers and Proteins","volume":"10","author":"Tsverava","year":"2024","journal-title":"Epilepsia Open"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1111\/j.1528-1167.2012.03631.x","article-title":"Sodium Channels and the Neurobiology of Epilepsy","volume":"53","author":"Oliva","year":"2012","journal-title":"Epilepsia"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sheilabi, M.A., Takeshita, L.Y., Sims, E.J., Falciani, F., and Princivalle, A.P. (2020). The Sodium Channel B4-Subunits Are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082955"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1146\/annurev.pharmtox.43.100901.140223","article-title":"Hormesis: The Dose-Response Revolution","volume":"43","author":"Calabrese","year":"2003","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Turrigiano, G. (2012). Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a005736"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"114911","DOI":"10.1016\/j.expneurol.2024.114911","article-title":"Collagen VI: Role in Synaptic Transmission and Seizure-Related Excitability","volume":"380","author":"Cifra","year":"2024","journal-title":"Exp. Neurol."},{"key":"ref_21","unstructured":"Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., and Delgado-Escueta, A.V. (2012). Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Ion Channelopathy in Epilepsy, National Center for Biotechnology Information."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6660","DOI":"10.1523\/JNEUROSCI.23-16-06660.2003","article-title":"Distribution and Properties of Functional Postsynaptic Kainate Receptors on Neocortical Layer V Pyramidal Neurons","volume":"23","author":"Eder","year":"2003","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1113\/JP280879","article-title":"GluN3A NMDA Receptor Subunits: More Enigmatic than Ever?","volume":"600","author":"Crawley","year":"2022","journal-title":"J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7577","DOI":"10.1523\/JNEUROSCI.23-20-07577.2003","article-title":"Sodium Channel Beta4, a New Disulfide-Linked Auxiliary Subunit with Similarity to Beta2","volume":"23","author":"Yu","year":"2003","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/43119","article-title":"K+ Channel Regulation of Signal Propagation in Dendrites of Hippocampal Pyramidal Neurons","volume":"387","author":"Hoffman","year":"1997","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1080\/15592294.2019.1638701","article-title":"DNA Hypermethylation in Disease: Mechanisms and Clinical Relevance","volume":"14","author":"Ehrlich","year":"2019","journal-title":"Epigenetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrg2485","article-title":"The Many Roles of Histone Deacetylases in Development and Physiology: Implications for Disease and Therapy","volume":"10","author":"Haberland","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.1074\/jbc.M110.146860","article-title":"Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-Jun Expression through a Deacetylase-Independent Mechanism","volume":"286","author":"Ma","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Qian, W., Yu, C., Wang, S., Niu, A., Shi, G., Cheng, Y., Xu, N., Jin, Q., and Jing, X. (2020). Depressive-Like Behaviors Induced by Chronic Social Defeat Stress Are Associated With HDAC7 Reduction in the Nucleus Accumbens. Front. Psychiatry, 11.","DOI":"10.3389\/fpsyt.2020.586904"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tsverava, L., Lordkipanidze, T., Lepsveridze, E., Nozadze, M., Kikvidze, M., and Solomonia, R. (2016). Myoinositol Attenuates the Cell Loss and Biochemical Changes Induced by Kainic Acid Status Epilepticus. Biomed Res. Int., 2016.","DOI":"10.1155\/2016\/2794096"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.tplants.2024.01.006","article-title":"LncRNAs: The Art of Being Influential without Protein","volume":"29","author":"Gonzales","year":"2024","journal-title":"Trends Plant Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.molcel.2021.11.017","article-title":"The Long Noncoding RNA GlycoLINC Assembles a Lower Glycolytic Metabolon to Promote Glycolysis","volume":"82","author":"Zhu","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Manna, I., Fortunato, F., De Benedittis, S., Sammarra, I., Bertoli, G., Labate, A., and Gambardella, A. (2022). Non-Coding RNAs: New Biomarkers and Therapeutic Targets for Temporal Lobe Epilepsy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063063"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1111\/epi.17937","article-title":"Emerging Roles of Long Non-Coding RNAs in Human Epilepsy","volume":"65","author":"Yazarlou","year":"2024","journal-title":"Epilepsia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.1523\/JNEUROSCI.23-09-03916.2003","article-title":"Increased Seizure Susceptibility and Proconvulsant Activity of Anandamide in Mice Lacking Fatty Acid Amide Hydrolase","volume":"23","author":"Clement","year":"2003","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0013-4694(72)90177-0","article-title":"Modification of Seizure Activity by Electrical Stimulation. II. Motor Seizure","volume":"32","author":"Racine","year":"1972","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref_37","unstructured":"Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates, Academic Press. [4th ed.]."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/297681a0","article-title":"Place Navigation Impaired in Rats with Hippocampal Lesions","volume":"297","author":"Morris","year":"1982","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ibneur.2024.01.009","article-title":"Long-Term Effects of Myo-Inositol on Traumatic Brain Injury: Epigenomic and Transcriptomic Studies","volume":"16","author":"Oganezovi","year":"2024","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41587-020-0439-x","article-title":"The Nf-Core Framework for Community-Curated Bioinformatics Pipelines","volume":"38","author":"Ewels","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D948","DOI":"10.1093\/nar\/gkae1071","article-title":"Ensembl 2025","volume":"53","author":"Dyer","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast Universal RNA-Seq Aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon Provides Fast and Bias-Aware Quantification of Transcript Expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1093\/bioinformatics\/btr167","article-title":"Bismark: A Flexible Aligner and Methylation Caller for Bisulfite-Seq Applications","volume":"27","author":"Krueger","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: Tool for the Unification of Biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"ClusterProfiler: An R Package for Comparing Biological Themes among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma Powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"E3290","DOI":"10.1073\/pnas.1606348113","article-title":"Osmoregulatory Inositol Transporter SMIT1 Modulates Electrical Activity by Adjusting PI(4,5)P2 Levels","volume":"113","author":"Dai","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/cns3.70029","article-title":"The Use of Synaptic Extracellular Myo-Inositol to Treat Developmental and Epileptic Encephalopathy","volume":"3","author":"Vos","year":"2025","journal-title":"Ann. Child Neurol. Soc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:25:53Z","timestamp":1763529953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":51,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211102"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211102","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]}}}