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The Promising Epigenetic Regulators for Refractory Epilepsy: An Adventurous Road Ahead

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Abstract

The attribution of seizure freedom is yet to be achieved for patients suffering from refractory epilepsy, e.g. Dravet Syndrome (DS). The confined ability of mono-chemical entity-based antiseizure drugs (ASDs) to act directly at genomic level is one of the factors, combined with undetermined seizure triggers lead to recurrent seizure (RS) in DS, abominably affecting the sub-genomic architecture of neural cells. Thus, the RS and ASD appear to be responsible for the spectrum of exorbitant clinical pathology. The RS distresses the 5-HT-serotonin pathway, hypomethylates genes of CNS, and modulates the microRNA (miRNA)/long non-coding RNA (lncRNA), eventually leading to frozen molecular alterations. These changes shall be reverted by compatible epigenetic regulators (EGR) like, miRNA and lncRNA from Breast milk (BML) and Bacopa monnieri (BMI). The absence of studious seizure in SCN1A mutation-positive babies for the first 6 months raises the possibility that the consequences of mutation in SCN1A are subsidized by EGRs from BML. EGR-dependent-modifier gene effect is likely imposed by the other members of the SCN family. Therefore, we advocate that miRNA/lncRNA from BML and bacosides/miRNA from BMI buffer the effect of SCN1A mutation by sustainably maintaining modifier gene effect in the aberrant neurons. The presence of miRNA-155-5p, -30b-5p, and -30c-5p family in BML and miR857, miR168, miR156, and miR158 in BMI target at regulating SCN family and CLCN5 as visualized by Cystoscope. Thus, we envisage that the possible effects of EGR might include (a) upregulating the haploinsufficient SCN1A strand, (b) down-regulating seizure-elevated miRNA, (c) suppressing the seizure-induced methyltransferases, and (d) enhancing the GluN2A subunit of NMDA receptor to improve cognition. The potential of these EGRs from BML and BML is to further experimentally strengthen, long-haul step forward in molecular therapeutics.

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References

  • Alamgir, A. N. M., Rahman, A., & Rahman, M. (2014). Secondary metabolites and antioxidant activity of the crude leaf extract of Bacopa monniera (L.) Pennel and Coccinia grandis (L.) J Voigt. Journal of Pharmacognosy and Phytochemistry, 3(1), 226–230.

    Google Scholar 

  • Alsaweed, M. (2015). Characterization of the miRNA content of human milk: novel molecules with multifunctional significance for the mother and the infant Characterization of the miRNA content of human milk: Novel molecules with multifunctional significance for the mother an (November).

  • Alsaweed, M., Hartmann, P. E., Geddes, D. T., & Kakulas, F. (2015). MicroRNAs in breastmilk and the lactating breast: potential immunoprotectors and developmental regulators for the infant and the mother. International Journal of Environmental Research and Public Health, 12(11), 13981–14020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alsaweed, M., Lai, C. T., Hartmann, P. E., & Geddes, D. T. (2016). Human milk miRNAs primarily originate from the mammary gland resulting in unique miRNA profiles of fractionated milk. Nature Publishing Group, 2015, 1–13.

    Google Scholar 

  • Anderson, L. L., Hawkins, N. A., Thompson, C. H., Kearney, J. A., & George, A. L. (2017). Unexpected efficacy of a novel sodium channel modulator in Dravet syndrome. Scientific Reports, 7(1), 1–9.

    Article  Google Scholar 

  • Anthony, K. (2022). RNA-based therapeutics for neurological diseases. RNA Biology, 19(1), 176–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barry, G., Brigg, J. A., Hwang, D. W., Nayler, S. P., Fortuna, P. R. J., Jonkhout, N., et al. (2017). The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states. Nature, 7, 1–11.

    CAS  Google Scholar 

  • Battaglia, D., Ricci, D., Chieffo, D., & Guzzetta, F. (2016). Outlining a core neuropsychological phenotype for Dravet syndrome. Epilepsy Research, 120, 91–97.

    Article  PubMed  Google Scholar 

  • Beamer, E., Fischer, W., & Engel, T. (2017). The ATP-gated P2X7 receptor as a target for the treatment of drug-resistant epilepsy. Frontiers in Neuroscience, 11, 1–9.

    Article  Google Scholar 

  • Bellato, M., De Marchi, D., Gualtieri, C., Sauta, E., Magni, P., Macovei, A., & Pasotti, L. (2019). A bioinformatics approach to explore microRNAs as tools to bridge pathways between plants and animals. Is DNA damage response (DDR) a potential target process? Frontiers in Plant Science, 10, 1–18.

    Article  Google Scholar 

  • Bender, A. C., Natola, H., Ndong, C., Holmes, G. L., Scott, R. C., & Lenck-Santini, P. P. (2013). Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiology of Disease, 54, 297–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berger, T. C., Vigeland, M. D., Hjorthaug, H. S., Etholm, L., Nome, C. G., Taubøll, E., et al. (2019). Neuronal and glial DNA methylation and gene expression changes in early epileptogenesis. PLoS ONE, 14, 1.

    Article  Google Scholar 

  • Berson, A., Nativio, R., Berger, S. L., & Bonini, N. M. (2018). Epigenetic regulation in neurodegenerative diseases. Trends in Neurosciences, 41(9), 587–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boison, D. (2016). The biochemistry and epigenetics of epilepsy: focus on adenosine and glycine. Frontiers in Molecular Neuroscience, 9(April), 1–7.

    Google Scholar 

  • Brennan, G. P., & Henshall, D. C. (2018). microRNAs in the pathophysiology of epilepsy. Neuroscience Letters, 667, 47–52.

    Article  CAS  PubMed  Google Scholar 

  • Brennan, G. P., & Henshall, D. C. (2020). MicroRNAs as regulators of brain function and targets for treatment of epilepsy. Nature Reviews Neurology, 16(9), 506–519.

    Article  CAS  PubMed  Google Scholar 

  • Briggs, J. A., Wolvetang, E. J., Mattick, J. S., Rinn, J. L., & Barry, G. (2015). Review mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron, 88(5), 861–877.

    Article  CAS  PubMed  Google Scholar 

  • Brodie, M. J., Besag, F., Ettinger, A. B., Mula, M., Gobbi, G., Comai, S., et al. (2016). Epilepsy, antiepileptic drugs, and aggression: An evidence-based review. Pharmacological Reviews, 68(3), 563–602.

    Article  PubMed  PubMed Central  Google Scholar 

  • Calhoun, J. D., Hawkins, N. A., Zachwieja, N. J., & Kearney, J. A. (2017). Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome. Epilepsia, 58(8), e111–e115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casanova, J. R., Nishimura, M., Owens, J. W., & Swann, J. W. (2012). Impact of seizures on developing dendrites: Implications for intellectual developmental disabilities. Epilepsia, 53(SUPPL. 1), 116–124.

    Article  PubMed  Google Scholar 

  • Catterall, W. A. (2014). Sodium channels, inherited epilepsy, and antiepileptic drugs. Annual Review of Pharmacology and Toxicology, 54(1), 317–338.

    Article  CAS  PubMed  Google Scholar 

  • Catterall, W. A. (2018). Dravet syndrome: A sodium channel interneuronopathy. Current Opinion in Physiology, 2, 42–50.

    Article  PubMed  Google Scholar 

  • Chalei, V., Sansom, S. N., Kong, L., Lee, S., Montiel, J. F., Vance, K. W., & Ponting, C. P. (2014). The Long Non-Coding RNA Dali is an Epigenetic Regulator of Neural Differentiation, 1, 1–24.

    Google Scholar 

  • Chang, P., Augustin, K., Boddum, K., Williams, S., Sun, M., Terschak, J. A., et al. (2016). Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain, 139(2), 431–443.

    Article  PubMed  Google Scholar 

  • Chen, W., Liu, J., Zhang, L., Xu, H., Guo, X., Deng, S., et al. (2014). Generation of the SCN1A epilepsy mutation in hiPS cells using the TALEN technique. Scientific Reports, 4, 1–7.

    Google Scholar 

  • Cho, C. H. (2011). Frontier of epilepsy research - motor signaling pathway. Experimental and Molecular Medicine, 43(5), 231–274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clossen, B. L., & Reddy, D. S. (2017a). Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy. Biochimica Et Biophysica Acta - Molecular Basis of Disease, 1863(6), 1519–1538.

    Article  CAS  PubMed  Google Scholar 

  • Clossen, B. L., & Reddy, D. S. (2017b). Biochimica et Biophysica Acta Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy. BBA - Molecular Basis of Disease, 1863(6), 1519–1538.

    Article  CAS  PubMed  Google Scholar 

  • Cook, A. M., & Bensalem-Owen, M. K. (2011). Mechanisms of action of antiepileptic drugs. Therapy, 8(3), 307–313.

    Article  CAS  Google Scholar 

  • Date, R. A. (2010). Bradyrhizobium effectiveness responses in Stylosanthes hamata and S. seabrana. Tropical Grasslands, 44(3), 141–157.

    Google Scholar 

  • De Jonghe, P. (2011). Molecular genetics of Dravet syndrome. Developmental Medicine and Child Neurology, 53(SUPPL. 2), 7–10.

    Article  PubMed  Google Scholar 

  • De Rubeis, S., He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Cicek, A. E., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515(7526), 209–215.

    Article  PubMed  PubMed Central  Google Scholar 

  • Deng, H., Zheng, W., & Song, Z. (2018). The genetics and molecular biology of fever-associated seizures or epilepsy. Expert Reviews in Molecular Medicine, 20, e3.

    Article  PubMed  Google Scholar 

  • Dinday, M. T., & Baraban, S. C. (2015). Large-scale phenotype-based antiepileptic drug screening in a zebrafish model of Dravet syndrome. eNeuro, 2(4), 1–19.

    Article  Google Scholar 

  • Djémié, T., Weckhuysen, S., von Spiczak, S., Carvill, G. L., Jaehn, J., Anttonen, A.-K., et al. (2016). Pitfalls in genetic testing: The story of missed SCN1A mutations. Molecular Genetics & Genomic Medicine, 4(4), 457–464.

    Article  Google Scholar 

  • Dravet, C. (2011). The core Dravet syndrome phenotype. Epilepsia, 52(SUPPL. 2), 3–9.

    Article  PubMed  Google Scholar 

  • Eid, T., Ghosh, A., Wang, Y., Beckström, H., Zaveri, H. P., Lee, T. S. W., et al. (2008). Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain, 131(8), 2061–2070.

    Article  PubMed  PubMed Central  Google Scholar 

  • El-Brolosy, M. A., Kontarakis, Z., Rossi, A., Kuenne, C., Günther, S., Fukuda, N., et al. (2019). Genetic compensation triggered by mutant mRNA degradation. Nature, 568(7751), 193–197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fisher, R. S., Cross, J. H., D’Souza, C., French, J. A., Haut, S. R., Higurashi, N., et al. (2018). Instruction manual for the ILAE 2017 operational classification of seizure types. Zeitschrift Fur Epileptologie, 31(4), 282–295.

    Article  Google Scholar 

  • Gadhavi, H., Patel, M., Mangukia, N., Shah, K., Bhadresha, K., Patel, S. K., et al. (2020). Transcriptome-wide miRNA identification of Bacopa monnieri: a cross-kingdom approach. Plant Signaling and Behavior, 15, 1.

    Article  Google Scholar 

  • Garofalo, S., Cornacchione, M., & Costanzo, A. D. (2012). From genetics to genomics of epilepsy. Neurology Research International., 2012, 876234.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ghasemi, M., & Schachter, S. C. (2011). The NMDA receptor complex as a therapeutic target in epilepsy: A review. Epilepsy and Behavior, 22(4), 617–640.

    Article  PubMed  Google Scholar 

  • Goff, K. M., & Goldberg, E. M. (2019). Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome. eLife, 8, 1–28.

    Article  Google Scholar 

  • Griffin, A., Hamling, K. R., Knupp, K., Hong, S. G., Lee, L. P., & Baraban, S. C. (2017). Clemizole and modulators of serotonin signaling suppress seizures in Dravet syndrome. Brain, 140(3), 669–683.

    PubMed  PubMed Central  Google Scholar 

  • Gross, C. (2017). MicroRNAs in epilepsy. Lancet Neurology, 15(13), 1368–1376.

    Google Scholar 

  • Guerrini, R., & Oguni, H. (2011). Borderline Dravet syndrome: A useful diagnostic category? Epilepsia, 52(SUPPL. 2), 10–12.

    Article  PubMed  Google Scholar 

  • Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., et al. (2017). High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. American Journal of Human Genetics, 101(5), 664–685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han, Z., Chen, C., Christiansen, A., Ji, S., Lin, Q., Anumonwo, C., et al. (2020). Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Science Translational Medicine, 12, 558.

    Article  Google Scholar 

  • Hansen, K. F., Sakamoto, K., Pelz, C., Impey, S., & Obrietan, K. (2014). Profiling status epilepticus-induced changes in hippocampal RNA expression using high-throughput RNA sequencing. Scientific Report, 4, 6930.

    Article  Google Scholar 

  • Hanson, J. E., Ma, K., Elstrott, J., Weber, M., Saillet, S., Scearce-levie, K., & Palop, J. J. (2020). GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Article GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models (pp. 381–396).

  • Harkin, L. A., McMahon, J. M., Iona, X., Dibbens, L., Pelekanos, J. T., Zuberi, S. M., et al. (2007). The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain, 130(3), 843–852.

    Article  PubMed  Google Scholar 

  • Hatini, P. G., & Commons, K. G. (2019). Serotonin abnormalities in Dravet syndrome mice before and after the age of seizure onset. Brain Research, 1724, 1.

    Article  Google Scholar 

  • Hawkins, N. A., Lewis, M., Hammond, R. S., Doherty, J. J., & Kearney, J. A. (2017). The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model. Scientific Reports, 7(1), 1–8.

    Article  CAS  Google Scholar 

  • Hawkins, N. A., Zachwieja, N. J., Miller, A. R., Anderson, L. L., & Kearney, J. A. (2016). Fine mapping of a Dravet syndrome modifier locus on mouse chromosome 5 and candidate gene analysis by RNA-Seq. PLoS Genetics, 12(10), 1–15.

    Article  Google Scholar 

  • Henshall, D. C. (2014). MicroRNA and epilepsy: Profiling, functions and potential clinical applications. Current Opinion in Neurology, 27(2), 199–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsiao, J., Yuan, T. Y., Tsai, M. S., Lu, C. Y., Lin, Y. C., Lee, M. L., et al. (2016). Upregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndrome. eBioMedicine, 9, 257–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu, Z.-Y., Wang, H.-Y., & Wang, Y. (2017). Recent progress in identifying genetic and epigenetic contributions to epilepsy. Reproductive and Developmental Medicine, 1(4), 239.

    Article  Google Scholar 

  • Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols, 4(1), 44–57.

    Article  CAS  PubMed  Google Scholar 

  • Huang, L. G., Zou, J., & Lu, Q. C. (2018). Silencing rno-miR-155-5p in rat temporal lobe epilepsy model reduces pathophysiological features and cell apoptosis by activating Sestrin-3. Brain Research, 1689, 109–122.

    Article  CAS  PubMed  Google Scholar 

  • Ibhazehiebo, K., Gavrilovici, C., De La Hoz, C. L., Ma, S. C., Rehak, R., Kaushik, G., et al. (2018). A novel metabolism-based phenotypic drug discovery platform in zebrafish uncovers HDACs 1 and 3 as a potential combined anti-seizure drug target. Brain, 141(3), 744–761.

    Article  PubMed  PubMed Central  Google Scholar 

  • Imbrici, P., Liantonio, A., Camerino, G. M., De Bellis, M., Camerino, C., Mele, A., et al. (2016). Therapeutic approaches to genetic ion channelopathies and perspectives in drug discovery. Frontiers in Pharmacology, 7(MAY), 1–28.

    Google Scholar 

  • Jensen, M. P., Brunklaus, A., Dorris, L., Zuberi, S. M., Knupp, K. G., Galer, B. S., & Gammaitoni, A. R. (2017). The humanistic and economic burden of Dravet syndrome on caregivers and families: Implications for future research. Epilepsy and Behavior, 70, 104–109.

    Article  PubMed  Google Scholar 

  • Jeyabalan, N., & Clement, J. P. (2016). SYNGAP1: Mind the gap. Frontiers in Cellular Neuroscience, 10(February), 1–16.

    Google Scholar 

  • Joshi, S., & Kapur, J. (2018). Mechanisms of status epilepticus: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor hypothesis. Epilepsia, 59(2017), 78–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang, S. K., Hawkins, N. A., & Kearney, J. A. (2019). C57BL / 6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a +/− mouse model of Dravet syndrome. Epilepsia Open, 2018, 164–169.

    Article  Google Scholar 

  • Karlsson, O., Rodosthenous, R. S., Jara, C., Brennan, K. J., Wright, R. O., Baccarelli, A. A., & Wright, R. J. (2016). Detection of long non-coding RNAs in human breastmilk extracellular vesicles: Implications for early child development. Epigenetics, 11(10), 721–729.

    Article  PubMed  PubMed Central  Google Scholar 

  • Khan, R., Krishnakumar, A., & Paulose, C. S. (2008). Decreased glutamate receptor binding and NMDA R1 gene expression in hippocampus of pilocarpine-induced epileptic rats: Neuroprotective role of Bacopa monnieri extract. Epilepsy and Behavior, 12(1), 54–60.

    Article  PubMed  Google Scholar 

  • Knupp, K. G., & Wirrell, E. C. (2018). Treatment strategies for Dravet syndrome. CNS Drugs, 32(4), 335–350.

    Article  CAS  PubMed  Google Scholar 

  • Kobow, K., & Blümcke, I. (2012). The emerging role of DNA methylation in epileptogenesis. Epilepsia, 53, 11–20.

    Article  CAS  PubMed  Google Scholar 

  • Kosaka, N., Izumi, H., Sekine, K., & Ochiya, T. (2010). MicroRNA as a new immune-regulatory agent in breast milk. Silence, 1(1), 1–8.

    Article  Google Scholar 

  • Kovács, R., Gerevich, Z., Friedman, A., Otáhal, J., Prager, O., Gabriel, S., & Berndt, N. (2018). Bioenergetic mechanisms of seizure control. Frontiers in Cellular Neuroscience, 12(October), 1–14.

    Google Scholar 

  • Krishnakumar, A., Abraham, P. M., Paul, J., & Paulose, C. S. (2009a). Down-regulation of cerebellar 5-HT2C receptors in pilocarpine-induced epilepsy in rats: Therapeutic role of Bacopa monnieri extract. Journal of the Neurological Sciences, 284(1–2), 124–128.

    Article  CAS  PubMed  Google Scholar 

  • Krishnakumar, A., Anju, T. R., Abraham, P. M., & Paulose, C. S. (2014). Alteration in 5-HT2C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: Restorative role of Bacopa monnieri. Neurochemical Research, 40(1), 216–225.

    Article  PubMed  Google Scholar 

  • Krishnakumar, A., Nandhu, M. S., & Paulose, C. S. (2009b). Upregulation of 5-HT2Creceptors in hippocampus of pilocarpine-induced epileptic rats: Antagonism by Bacopa monnieri. Epilepsy and Behavior, 16(2), 225–230.

    Article  PubMed  Google Scholar 

  • Kumar, M. G., Rowley, S., Fulton, R., Dinday, M. T., Baraban, S. C., & Patel, M. (2016). Altered glycolysis and mitochondrial respiration in a zebrafish model of Dravet syndrome. eNeuro, 3(2), 1–12.

    Article  CAS  Google Scholar 

  • Lamar, T., Vanoye, C. G., Calhoun, J., Wong, J. C., Dutton, S. B. B., Jorge, B. S., et al. (2017). SCN3A deficiency associated with increased seizure susceptibility. Neurobiology of Disease, 102, 38–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laxer, K. D., Trinka, E., Hirsch, L. J., Cendes, F., Langfitt, J., Delanty, N., et al. (2014). The consequences of refractory epilepsy and its treatment. Epilepsy & Behavior, 37, 59–70.

    Article  Google Scholar 

  • Lenk, G. M., Jafar-nejad, P., Hill, S. F., Huffman, L. D., Smolen, C. E., Wagnon, J. L., et al. (2020). Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and Dravet syndrome. Annals in Neurology, 87, 339–346.

    Article  CAS  Google Scholar 

  • Levin, A. A. (2019). Treating disease at the RNA level with oligonucleotides. New England Journal of Medicine, 380(1), 57–70.

    Article  PubMed  Google Scholar 

  • Li, T., Kuang, Y., & Li, B. (2016). The genetic variants in 3’ untranslated region of voltage-gated sodium channel alpha 1 subunit gene affect the mRNA-microRNA interactions and associate with epilepsy. BMC Genetics, 17(1), 1–12.

    Article  Google Scholar 

  • Lin, G. W., Lu, P., Zeng, T., Tang, H. L., Chen, Y. H., Liu, S. J., et al. (2017). GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions. Neuropharmacology, 113, 480–489.

    Article  CAS  PubMed  Google Scholar 

  • Liu, H., Roy, M., & Tian, F. F. (2013). MicroRNA-based therapy: A new dimension in epilepsy treatment. International Journal of Neuroscience, 123(9), 617–622.

    Article  CAS  PubMed  Google Scholar 

  • Liu, J., Gao, C., Chen, W., Ma, W., Li, X., Shi, Y., et al. (2016). CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: Mechanism of epilepsy caused by an SCN1A loss-of-function mutation. Translational Psychiatry, 6, 2015.

    Article  Google Scholar 

  • Lourhmati, A., Buniatian, G. H., Paul, C., Verleysdonk, S., Buecheler, R., Buadze, M., et al. (2013). Age-dependent astroglial vulnerability to hypoxia and glutamate: The role for erythropoietin. PLoS ONE, 8(10), 1–16.

    Article  Google Scholar 

  • Lukasik, A., Brzozowska, I., Zielenkiewicz, U., & Zielenkiewicz, P. (2018). Detection of plant miRNAs abundance in human breast milk. International Journal of Molecular Sciences, 19, 1. https://doi.org/10.3390/ijms19010037

    Article  CAS  Google Scholar 

  • Manuscript, A. (2010). Rakhade - 2009 - Nat Rev Neurol.pdf, 5(7).

  • Margari, L., Legrottaglie, A. R., Vincenti, A., Coppola, G., Operto, F. F., Buttiglione, M., et al. (2018). Association between SCN1A gene polymorphisms and drug resistant epilepsy in pediatric patients. Seizure, 55, 30–35.

    Article  PubMed  Google Scholar 

  • Marini, C., Scheffer, I. E., Nabbout, R., Suls, A., De Jonghe, P., Zara, F., & Guerrini, R. (2011). The genetics of Dravet syndrome. Epilepsia, 52(SUPPL. 2), 24–29.

    Article  CAS  PubMed  Google Scholar 

  • Martin, M. S., Tang, B., Papale, L. A., Yu, F. H., Catterall, W. A., & Escayg, A. (2007). The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Human Molecular Genetics, 16(23), 2892–2899.

    Article  CAS  PubMed  Google Scholar 

  • Mathew, J., Balakrishnan, S., Antony, S., Abraham, P., & Paulose, C. S. (2012). Decreased GABA receptor in the cerebral cortex of epileptic rats: Effect of Bacopa monnieri and Bacoside-A. Journal of Biomedical Science, 19(1), 25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathew, J., Peeyush Kumar, T., Khan, R. S., & Paulose, C. S. (2010). Behavioral deficit and decreased GABA receptor functional regulation in the cerebellum of epileptic rats: Effect of Bacopa monnieri and bacoside A. Epilepsy and Behavior, 17(4), 441–447.

    Article  PubMed  Google Scholar 

  • Mathur, D., Goyal, K., Koul, V., & Anand, A. (2016). The molecular links of re-emerging therapy: A review of evidence of Brahmi (Bacopa). Frontiers in Pharmacology, 7, 1–15.

    Article  Google Scholar 

  • Mazarati, A., Siddarth, P., Baldwin, R. A., Shin, D., Caplan, R., & Sankar, R. (2008). Depression after status epilepticus: Behavioral and biochemical deficits and effects of fluoxetine. Brain, 131(8), 2071–2083.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mei, S., Feng, W., Zhu, L., Yu, Y., Yang, W., Gao, B., et al. (2017). Genetic polymorphisms and valproic acid plasma concentration in children with epilepsy on valproic acid monotherapy. Seizure, 51, 22–26.

    Article  PubMed  Google Scholar 

  • Meldrum, B. S., & Rogawski, M. A. (2011). On the Origin of Interictal Activity in Human Temporal Lobe Epilepsy in Vitro, 4(January), 1.

    Google Scholar 

  • Melnik, B. C. (2017). Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer. Nutrition and Metabolism, 14, 1–12.

    Google Scholar 

  • Melnik, B. C., & Kakulas, F. (2019). Milk exosomes and MicroRNAs: Potential epigenetic regulators. Handbook of Nutrition, Diet, and Epigenetics, 3, 1467–1494.

    Article  Google Scholar 

  • Melnik, B. C., Schmitz, G., Hartwig, F. P., De Mola, C. L., Davies, N. M., Victora, C. G., et al. (2017). Milk’s role as an epigenetic regulator in health and disease. Handbook of Nutrition, Diet, and Epigenetics, 12(1), 1467–1494.

    Google Scholar 

  • Miller-Delaney, S. F. C., Das, S., Sano, T., Jimenez-Mateos, E. M., Bryan, K., Buckley, P. G., et al. (2012). Differential DNA methylation patterns define status epilepticus and epileptic tolerance. Journal of Neuroscience, 32(5), 1577–1588.

    Article  CAS  PubMed  Google Scholar 

  • Mills, J. D., van Vliet, E. A., Chen, B. J., Janitz, M., Anink, J. J., Baayen, J. C., et al. (2020). Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs. Neurobiology of Disease, 134, 104612.

    Article  CAS  PubMed  Google Scholar 

  • Mishra, A., Mishra, A. K., & Jha, S. (2018). Effect of traditional medicine brahmi vati and bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrazol-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory animals. Epilepsy and Behavior, 80, 144–151.

    Article  PubMed  Google Scholar 

  • Muir, A. M., King, C., Schneider, A. L., Buttar, A. S., Scheffer, I. E., Sadleir, L. G., & Mefford, H. C. (2019). Double somatic mosaicism in a child with Dravet syndrome. Neurology Genetics, 5, 3.

    Article  Google Scholar 

  • Nemetchek, M. D., Stierle, A. A., Stierle, D. B., & Lurie, D. I. (2017). The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. Journal of Ethnopharmacology, 197, 92–100.

    Article  PubMed  Google Scholar 

  • Oakley, J. C., Kalume, F., Yu, F. H., Scheuer, T., & Catterall, W. A. (2009). Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proceedings of the National Academy of Sciences, 106(10), 3994–3999.

    Article  CAS  Google Scholar 

  • Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., et al. (2007). Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: A circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. Journal of Neuroscience, 27(22), 5903–5914.

    Article  CAS  PubMed  Google Scholar 

  • Oikawa, H., Goh, W. W. B., Lim, V. K. J., Wong, L., & Sng, J. C. G. (2015). Valproic acid mediates miR-124 to down-regulate a novel protein target, GNAI1. Neurochemistry International, 91, 62–71.

    Article  CAS  PubMed  Google Scholar 

  • Peschansky, V. J., Pastori, C., Zeier, Z., Wentzel, K., Velmeshev, D., Magistri, M., et al. (2016). Molecular and cellular neuroscience: The long non-coding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans. Molecular and Cellular Neuroscience, 74, 49–57.

    Article  CAS  PubMed  Google Scholar 

  • Preethi, J., Singh, H. K., Charles, P. D., & Emmanuvel Rajan, K. (2012). Participation of microRNA 124-CREB pathway: a parallel memory enhancing mechanism of standardisedstandardized extract of Bacopa monniera (BESEB CDRI-08). Neurochemical Research, 37(10), 2167–2177.

    Article  CAS  PubMed  Google Scholar 

  • Pulido Fontes, L., et al. (2015). Epigenetics and epilepsy [Epigenética y epilepsia]. Neurología, 30(2), 111–118.

    Article  CAS  PubMed  Google Scholar 

  • Puranik, Y. G., Birnbaum, A. K., Marino, S. E., Ahmed, G., Cloyd, J. C., Remmel, R. P., et al. (2013). Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics, 14(1), 35–45.

    Article  CAS  PubMed  Google Scholar 

  • Quan, Z., Zheng, D., & Qing, H. (2017). Regulatory roles of long non-coding RNAs in the central nervous system and associated. Neurodegenerative Disease, 11, 1.

    Google Scholar 

  • Rahnamoun, H., Orozco, P., & Lauberth, S. M. (2020). The role of enhancer RNAs in epigenetic regulation of gene expression. Transcription, 11(1), 19–25.

    Article  PubMed  Google Scholar 

  • Reddy, S. D., Clossen, B. C., & Reddy, D. S. (2017). Epigenetic histone deacetylation inhibition prevents the development and persistence of temporal lobe epilepsy. Journal of Pharmacology and Experimental Therapeutics, 364, 97–109.

    Article  PubMed  Google Scholar 

  • Reschke, C. R., Silva, L. F. A., Norwood, B. A., Senthilkumar, K., Morris, G., Sanz-Rodriguez, A., et al. (2017). Potent anti-seizure effects of locked nucleic acid antagomirs targeting miR-134 in multiple mouse and rat models of epilepsy. Molecular Therapy, 6(March), 45–56.

    CAS  PubMed  Google Scholar 

  • Rho, J. M. (2015). Clinical implications of basic research of inhibition of lactate dehydrogenase to treat epilepsy. New England Journal of Medicine, 373, 187–189.

    Article  PubMed  Google Scholar 

  • Rodríguez-Muñoz, M., Sánchez-Blázquez, P., & Garzón, J. (2018). Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget, 9(34), 23373–23389.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rogawski, M. A., & Löscher, W. (2004). The neurobiology of antiepileptic drugs. Nature Reviews Neuroscience, 5(7), 553–564.

    Article  CAS  PubMed  Google Scholar 

  • Rubinstein, M., Han, S., Tai, C., Westenbroek, R. E., Hunker, A., Scheuer, T., & Catterall, W. A. (2015). Dissecting the phenotypes of Dravet syndrome by gene deletion. Brain, 138(8), 2219–2233.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rusconi, R., Combi, R., Cestèle, S., Grioni, D., Franceschetti, S., Dalprà, L., & Mantegazza, M. (2009). A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: Common mechanism in Nav1.1 related epilepsies? Human Mutation, 30, 7.

    Article  Google Scholar 

  • Sada, N., Lee, S., Katsu, T., Otsuki, T., & Inoue, T. (2015a). Targeting LDH enzymes with a stiripentol analog to treat epilepsy–supplementary materials. Science, 347(6228), 1362–1367.

    Article  CAS  PubMed  Google Scholar 

  • Sada, N., Lee, S., Katsu, T., Otsuki, T., & Inoue, T. (2015b). Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science, 347(6228), 1362–1367.

    Article  CAS  PubMed  Google Scholar 

  • Sadleir, L. G., Mountier, E. I., Gill, D., Davis, S., Joshi, C., DeVile, C., et al. (2017). Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype. Neurology, 89(10), 1035–1042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salgueiro-Pereira, A. R., Duprat, F., Pousinha, P. A., Loucif, A., Douchamps, V., Regondi, C., et al. (2019). A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies. Neurobiology of Disease, 125, 31–44.

    Article  CAS  PubMed  Google Scholar 

  • Sanchis, V. (1993). Aplicaciones de las t??cnicas de biolog??a molecular para el control de la contaminaci??n por aflatoxinas. Microbiologia SEM, 9, 69–75.

    CAS  Google Scholar 

  • Sano, T., Reynolds, J. P., Jimenez-Mateos, E. M., Matsushima, S., Taki, W., & Henshall, D. C. (2012). MicroRNA-34a upregulation during seizure-induced neuronal death. Cell Death and Disease, 3(3), 1–8.

    Article  Google Scholar 

  • Schmidt, D., & Schachter, S. C. (2014). Drug treatment of epilepsy in adults. BMJ, 348, 1–18.

    Article  Google Scholar 

  • Silvado, C. E., Terra, V. C., & Twardowschy, C. A. (2018). CYP2C9 polymorphisms in epilepsy: Influence on phenytoin treatment. Pharmacogenomics and Personalized Medicine, 11, 51–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., et al. (2009). A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genetics, 5(9), 1–12.

    Article  CAS  Google Scholar 

  • Smith, R. S., Kenny, C. J., Ganesh, V., Jang, A., Borges-Monroy, R., Partlow, J. N., et al. (2018). Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development. Neuron, 99(5), 905–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stafstrom, C. E. (2010). Mechanisms of action of antiepileptic drugs: The search for synergy. Current Opinion in Neurology, 23(2), 157–163.

    Article  CAS  PubMed  Google Scholar 

  • Tai, C., Abe, Y., Westenbroek, R. E., Scheuer, T., & Catterall, W. A. (2014). Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. Proceedings of the National Academy of Sciences of the United States of America, 111(30), 3139–3148.

    Google Scholar 

  • Tan, N. N., Tang, H. L., Lin, G. W., Chen, Y. H., Lu, P., Li, H. J., et al. (2017). Epigenetic downregulation of scn3a expression by valproate: A possible role in its anticonvulsant activity. Molecular Neurobiology, 54(4), 2831–2842.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka, Y., Sone, T., Higurashi, N., Sakuma, T., Suzuki, S., Ishikawa, M., et al. (2018). Generation of D1–1 TALEN isogenic control cell line from Dravet syndrome patient iPSCs using TALEN-mediated editing of the SCN1A gene. Stem Cell Research, 28, 100–104.

    Article  CAS  PubMed  Google Scholar 

  • Tani, H., Imamachi, N., Mizutani, R., Imamura, K., Kwon, Y., Miyazaki, S., et al. (2015). Genome-wide analysis of long noncoding RNA turnover. Methods in Molecular Biology, 1262, 305–320.

    Article  CAS  PubMed  Google Scholar 

  • Tiwari, D., Peariso, K., & Gross, C. (2018). MicroRNA-induced silencing in epilepsy: Opportunities and challenges for clinical application. Developmental Dynamics, 247(1), 94–110.

    Article  CAS  PubMed  Google Scholar 

  • Ulitsky, I., & Bartel, D. P. (2013). Review lincRNAs: Genomics, evolution, and mechanisms. Cell, 154(1), 26–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valassina, N., Brusco, S., Salamone, A., Serra, L., Luoni, M., Giannelli, S., et al. (2022). Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome. Nature Communications, 13, 1.

    Article  Google Scholar 

  • Villas, N., Meskis, M. A., & Goodliffe, S. (2017). Dravet syndrome: Characteristics, comorbidities, and caregiver concerns. Epilepsy and Behavior, 74, 81–86.

    Article  PubMed  Google Scholar 

  • Wahlestedt, C. (2013). Targeting long non-coding RNA to therapeutically upregulate gene expression. Nature Reviews Drug Discovery, 12(6), 433–446.

    Article  CAS  PubMed  Google Scholar 

  • Wilmshurst, J. M., Berg, A. T., Lagae, L., Newton, C. R., & Cross, J. H. (2014). The challenges and innovations for therapy in children with epilepsy. Nature Reviews Neurology, 10(5), 249–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wirrell, E. C. (2016). Treatment of Dravet syndrome. Canadian Journal of Neurological Sciences, 43(S3), S13–S18.

    Article  Google Scholar 

  • Wong, J. C., Dutton, S. B. B., Collins, S. D., Schachter, S., & Escayg, A. (2016). Huperzine a provides robust and sustained protection against induced seizures in Scn1a mutant mice. Frontiers in Pharmacology, 7, 1–14.

    Article  CAS  Google Scholar 

  • Wykes, R. C., & Lignani, G. (2018). Gene therapy and editing: Novel potential treatments for neuronal channelopathies. Neuropharmacology, 132, 108–117.

    Article  CAS  PubMed  Google Scholar 

  • Younus, I., & Reddy, D. S. (2017). Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy. Pharmacology and Therapeutics, 177, 108–122.

    Article  CAS  PubMed  Google Scholar 

  • Zamponi, G. W., Striessnig, J., Koschak, A., & Dolphin, A. C. (2015). The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacological Reviews, 67(4), 821–870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, Z., Wang, Z., Zhang, B., & Liu, Y. (2018). Downregulation of microRNA-155 by preoperative administration of valproic acid prevents postoperative seizures by upregulating SCN1A. Molecular Medicine Reports, 17(1), 1375–1381.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Chairman and Managing Director of Noorul Islam Centre for Higher Education and NIMS Medicity, respectively, for their generous support. We extend the gratitude to the authoritative Tamil author Jeyamohan Bhaguleyan Pillai for his narration about the brain (https://www.jeyamohan.in/129209/) that has been used in the last line of conclusion.

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  1. Vemparthan Suvekbala and Haribaskar Ramachandran have equal author contribution.

Authors and Affiliations

  1. Genetics and Molecular Diagnostics Laboratory, NIMS Medicity, Aaralumoodu Neyyattinkara, Thiruvananthapuram, Kerala, 695123, India

    Vemparthan Suvekbala

  2. Department of Biomedical Sciences and Technology, Noorul Islam Centre for Higher Education, Kumarakovil, Tamil Nadu, 629180, India

    Vemparthan Suvekbala

  3. EDII-Anna Business Incubation Research Foundation [A Section 8, Not-for-Profit Company] Anna University, BIT Campus, Trichy, Tamil Nadu, 620017, India

    Vemparthan Suvekbala

  4. Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108, Freiburg, Germany

    Haribaskar Ramachandran

  5. Department of Computational Biology, St. Jude Children’s Research Hospital, Danny Thomas Palace, Memphis, Tennesse, 38105, USA

    Alaguraj Veluchamy

  6. Department of Neurosurgery, Tamilnadu Government Multi-Super-Specialty Hospital, Omandurar Government Estate, Anna Salai, Chennai, 600002, India

    Mariano A. Bruno Mascarenhas

  7. Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur St SE, Atlanta, GA, 30303, USA

    Tharmarajan Ramprasath

  8. Child Development and Research Centre and Department of Neurology, SPECTRM, NIMS Medicity, Aaralumoodu, Neyyattinkara, Thiruvananthapuram, Kerala, 695123, India

    M. K. C. Nair

  9. Department of Emergency Medicine, Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Venkata Naga Srikanth Garikipati

  10. School of Health Sciences, University of Tasmania, Launceston, TAS, Australia

    Rohit Gundamaraju

  11. Department of Molecular Biology, School of Biological Sciences, Centre for Excellence in Genomic Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, 625021, India

    Ramasamy Subbiah

  12. Department of Biochemistry, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, India

    Ramasamy Subbiah

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Suvekbala, V., Ramachandran, H., Veluchamy, A. et al. The Promising Epigenetic Regulators for Refractory Epilepsy: An Adventurous Road Ahead. Neuromol Med 25, 145–162 (2023). https://doi.org/10.1007/s12017-022-08723-0

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