Status epilepticus (SE) is a common paediatric emergency with the highest incidence in the neonatal period and is a well-known epileptogenic insult. As previously established in various experimental and human studies, SE induces long-term alterations to brain metabolism, alterations that directly contribute to the development of epilepsy. To influence these changes, organic isothiocyanate compound sulforaphane (SFN) has been used in the present study for its known effect of enhancing antioxidative, cytoprotective, and metabolic cellular properties via the Nrf2 pathway. We have explored the effect of SFN in a model of acquired epilepsy induced by Li-Cl pilocarpine in immature rats (12 days old). Energy metabolites PCr, ATP, glucose, glycogen, and lactate were determined by enzymatic fluorimetric methods during the acute phase of SE. Protein expression was evaluated by Western blot (WB) analysis. Neuronal death was scored on the FluoroJadeB stained brain sections harvested 24 h after SE. To assess the effect of SFN on glucose metabolism we have performed a series of 18F-DG μCT/PET recordings 1 h, 1 day, and 3 weeks after the induction of SE. Responses of cerebral blood flow (CBF) to electrical stimulation and their influence by SFN were evaluated by laser Doppler flowmetry (LDF). We have demonstrated that the Nrf2 pathway is upregulated in the CNS of immature rats after SFN treatment. In the animals that had undergone SE, SFN was responsible for lowering glucose uptake in most regions 1 h after the induction of SE. Moreover, SFN partially reversed hypometabolism observed after 24 h and achieved full reversal at approximately 3 weeks after SE. Since no difference in cell death was observed in SFN treated group, these changes cannot be attributed to differences in neurodegeneration. SFN per se did not affect the glucose uptake at any given time point suggesting that SFN improves endogenous CNS ability to adapt to the epileptogenic insult. Furthermore, we had discovered that SFN improves blood flow and accelerates CBF response to electrical stimulation. Our findings suggest that SFN improves metabolic changes induced by SE which have been identified during epileptogenesis in various animal models of acquired epilepsy.

Department of Pathophysiology 2nd Faculty of Medicine Charles University Prague Czechia

Institute of Physiology Czech Academy of Sciences Prague Czechia

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Aguiar C. C. T., Almeida A. B., Arajo P. V. P., Abreu R. N. D. C., Chaves E. M. C., do Vale O. C., et al. (2012). Oxidative stress and epilepsy: literature review. Oxid. Med. Cell. Longev. 2012:795259. 10.1155/2012/795259 PubMed DOI PMC

Alfieri A., Srivastava S., Siow R. C. M., Cash D., Modo M., Duchen M. R., et al. (2013). Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke. Free Radic. Biol. Med. 65 1012–1022. 10.1016/j.freeradbiomed.2013.08.190 PubMed DOI

Arena A., Zimmer T. S., van Scheppingen J., Korotkov A., Anink J. J., Mühlebner A., et al. (2019). Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence. Brain Pathol. 29 351–365. 10.1111/bpa.12661 PubMed DOI PMC

Bazzigaluppi P., Amini A. E., Weisspapir I., Stefanovic B., Carlen P. L. (2017). Hungry neurons: metabolic insights on seizure dynamics. Int. J. Mol. Sci. 18:2269. 10.3390/ijms18112269 PubMed DOI PMC

Broekaart D. W. M., Anink J. J., Baayen J. C., Idema S., de Vries H. E., Aronica E., et al. (2018). Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression. Epilepsia 59 1931–1944. 10.1111/epi.14550 PubMed DOI

Carrasco-Pozo C., Tan K. N., Borges K. (2015). Sulforaphane is anticonvulsant and improves mitochondrial function. J. Neurochem. 135 932–942. 10.1111/jnc.13361 PubMed DOI

Citraro R., Leo A., Constanti A., Russo E., De Sarro G. (2016). MTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol. Res. 107 333–343. 10.1016/j.phrs.2016.03.039 PubMed DOI

Crino P. B. (2015). mTOR signaling in epilepsy: insights from malformations of cortical development. Cold Spring Harb. Perspect. Med. 5 1–18. 10.1101/cshperspect.a022442 PubMed DOI PMC

da Silva Fernandes M. J., Dubé C., Boyet S., Marescaux C., Nehlig A. (1999). Correlation between hypermetabolism and neuronal damage during status epilepticus induced by lithium and pilocarpine in immature and adult rats. J. Cerebr. Blood Flow Metab. 19 195–209. 10.1097/00004647-199902000-00011 PubMed DOI

Denzer I., Münch G., Friedland K. (2016). Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds. Pharmacol. Res. 103 80–94. 10.1016/j.phrs.2015.11.019 PubMed DOI

Dinkova-Kostova A. T., Abramov A. Y. (2015). The emerging role of Nrf2 in mitochondrial function. Free Radic. Biol. Med. 88 179–188. 10.1016/j.freeradbiomed.2015.04.036 PubMed DOI PMC

Dobbing J. (1970). Undernutrition and the developing brain: the relevance of animal models to the human problem. Am. J. Dis. Childr. 120 411–415. 10.1001/archpedi.1970.02100100075005 PubMed DOI

Druga R., Kubová H., Suchomelová L., Haugvicová R. (2003). Lithium/pilocarpine status epilepticus-induced neuropathology of piriform cortex and adjoining structures in rats is age-dependent. Physiol. Res. 52 251–264. PubMed

Dubé C., Boyet S., Marescaux C., Nehlig A. (2000). Progressive metabolic changes underlying the chronic reorganization of brain circuits during the silent phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. Exp. Neurol. 162 146–157. 10.1006/exnr.2000.7324 PubMed DOI

Dubé C., Boyet S., Marescaux C., Nehlig A. (2001). Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. Exp. Neurol. 167 227–241. 10.1006/exnr.2000.7561 PubMed DOI

Engel J. (1996). Introduction to temporal lobe epilepsy. Epilepsy Res. 26 141–150. 10.1016/S0920-1211(96)00043-5 PubMed DOI

Farrell J. S., Gaxiola-Valdez I., Wolff M. D., David L. S., Dika H. I., Geeraert B. L., et al. (2016). Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent. eLife 5: e19352. 10.7554/eLife.19352 PubMed DOI PMC

Folbergrová J., Druga R., Haugvicová R., Mareš P., Otáhal J. (2008). Anticonvulsant and neuroprotective effect of (S)-3,4-dicarboxyphenylglycine against seizures induced in immature rats by homocysteic acid. Neuropharmacology 54 665–675. 10.1016/j.neuropharm.2007.11.015 PubMed DOI

Folbergrová J., Ješina P., Drahota Z., Lisý V., Haugvicová R., Vojtíšková A., et al. (2007). Mitochondrial complex I inhibition in cerebral cortex of immature rats following homocysteic acid-induced seizures. Exp. Neurol. 204 597–609. 10.1016/j.expneurol.2006.12.010 PubMed DOI

Folbergrová J., Ješina P., Haugvicová R., Lisý V., Houštěk J. (2010). Sustained deficiency of mitochondrial complex I activity during long periods of survival after seizures induced in immature rats by homocysteic acid. Neurochem. Int. 56 394–403. 10.1016/j.neuint.2009.11.011 PubMed DOI

Folbergrová J., Ješina P., Kubová H., Otáhal J. (2018). Effect of resveratrol on oxidative stress and mitochondrial dysfunction in immature brain during epileptogenesis. Mol. Neurobiol. 55 7512–7522. 10.1007/s12035-018-0924-0 PubMed DOI

Folbergrová J., Ješina P., Kubová N., Druga R., Otáhal J. (2016). Status epilepticus in immature rats is associated with oxidative stress and mitochondrial dysfunction. Front. Cell. Neurosci. 10:136. 10.3389/fncel.2016.00136 PubMed DOI PMC

Folbergrová J., Ješina P., Otáhal J. (2021). Treatment with resveratrol ameliorates mitochondrial dysfunction during the acute phase of status epilepticus in immature rats. Front. Neurosci. 15:634378. 10.3389/fnins.2021.634378 PubMed DOI PMC

Folbergrová J., Kunz W. S. (2012). Mitochondrial dysfunction in epilepsy. Mitochondrion 12 35–40. 10.1016/j.mito.2011.04.004 PubMed DOI

Folbergrová J., Otáhal J., Druga R. (2012). Brain superoxide anion formation in immature rats during seizures: protection by selected compounds. Exp. Neurol. 233 421–429. 10.1016/j.expneurol.2011.11.009 PubMed DOI

Greco T., Shafer J., Fiskum G. (2011). Sulforaphane inhibits mitochondrial permeability transition and oxidative stress. Free Radic. Biol. Med. 51 2164–2171. 10.1016/j.freeradbiomed.2011.09.017 PubMed DOI PMC

Guo Y., Gao F., Wang S., Ding Y., Zhang H., Wang J., et al. (2009). In vivo mapping of temporospatial changes in glucose utilization in rat brain during epileptogenesis: an 18F-fluorodeoxyglucose-small animal positron emission tomography study. Neuroscience 162 972–979. 10.1016/j.neuroscience.2009.05.041 PubMed DOI

Gureev A. P., Shaforostova E. A., Popov V. N. (2019). Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Front. Genet. 10:435. 10.3389/fgene.2019.00435 PubMed DOI PMC

Hirtz D., Thurman D. J., Gwinn-Hardy K., Mohamed M., Chaudhuri A. R., Zalutsky R. (2007). How common are the “common” neurologic disorders? Neurology 68 326–337. 10.1212/01.wnl.0000252807.38124.a3 PubMed DOI

Holmström K. M., Baird L., Zhang Y., Hargreaves I., Chalasani A., Land J. M., et al. (2013). Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol. Open 2 761–770. 10.1242/bio.20134853 PubMed DOI PMC

Huisman M. C., van Golen L. W., Hoetjes N. J., Greuter H. N., Schober P., Ijzerman R. G., et al. (2012). Cerebral blood flow and glucose metabolism in healthy volunteers measured using a high-resolution PET scanner. EJNMMI Res. 2 1–9. 10.1186/2191-219X-2-63 PubMed DOI PMC

Imran I., Hillert M. H., Klein J. (2015). Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain. J. Neurochem. 135 1007–1018. 10.1111/jnc.13360 PubMed DOI

Innamorato N. G., Rojo A., I, García-Yagüe Á. J., Yamamoto M., de Ceballos M. L., Cuadrado A. (2008). The transcription factor Nrf2 is a therapeutic target against brain inflammation. J. Immunol. 181 680–689. 10.4049/jimmunol.181.1.680 PubMed DOI

Jiang J., Quan Y., Ganesh T., Pouliot W. A., Dudek F. E., Dingledine R. (2013). Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc. Natl. Acad. Sci. U.S.A. 110 3591–3596. 10.1073/pnas.1218498110 PubMed DOI PMC

Kann O., Kovács R., Njunting M., Behrens C. J., Otáhal J., Lehmann T. N., et al. (2005). Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans. Brain 128 2396–2407. 10.1093/brain/awh568 PubMed DOI

Knowlton R. C., Laxer K. D., Klein G., Sawrie S., Ende G., Hawkins R. A., et al. (2001). In vivo hippocampal glucose metabolism in mesial temporal lobe epilepsy. Neurology 57 1184–1190. 10.1212/WNL.57.7.1184 PubMed DOI

Kovács R., Gerevich Z., Friedman A., Otáhal J., Prager O., Gabriel S., et al. (2018). Bioenergetic mechanisms of seizure control. Front. Cell. Neurosci. 12:335. 10.3389/fncel.2018.00335 PubMed DOI PMC

Kovács R., Schuchmann S., Gabriel S., Kann O., Kardos J., Heinemann U. (2002). Free radical-mediated cell damage after experimental status epilepticus in hippocampal slice cultures. J. Neurophysiol. 88 2909–2918. 10.1152/jn.00149.2002 PubMed DOI

Kubo E., Chhunchha B., Singh P., Sasaki H., Singh D. P. (2017). Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress. Sci. Rep. 7 1–17. 10.1038/s41598-017-14520-8 PubMed DOI PMC

Kudin A. P., Bimpong-Buta N. Y. B., Vielhaber S., Elger C. E., Kunz W. S. (2004). Characterization of superoxide-producing sites in isolated brain mitochondria. J. Biol. Chem. 279 4127–4135. 10.1074/jbc.M310341200 PubMed DOI

Kunz W. S., Kudin A. P., Vielhaber S., Blümcke I., Zuschratter W., Schramm J., et al. (2000). Mitochondrial complex I deficiency in the epileptic focus of patients with temporal lobe epilepsy. Ann. Neurol. 48 766–773. 10.1002/1531-8249(200011)48:5<766::aid-ana10>3.0.co;2-m PubMed DOI

Kwak M.-K., Wakabayashi N., Greenlaw J. L., Yamamoto M., Kensler T. W. (2003). Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol. Cell. Biol. 23 8786–8794. 10.1128/mcb.23.23.8786-8794.2003 PubMed DOI PMC

Laschet J. J., Minier F., Kurcewicz I., Bureau M. H., Trottier S., Jeanneteau F., et al. (2004). Glyceraldehyde-3-phosphate dehydrogenase is a GABAA receptor kinase linking glycolysis to neuronal inhibition. J. Neurosci. 24 7614–7622. 10.1523/JNEUROSCI.0868-04.2004 PubMed DOI PMC

Lee E. M., Park G. Y., Im K. C., Kim S. T., Woo C. W., Chung J. H., et al. (2012). Changes in glucose metabolism and metabolites during the epileptogenic process in the lithium-pilocarpine model of epilepsy. Epilepsia 53 860–869. 10.1111/j.1528-1167.2012.03432.x PubMed DOI

Lee H. G., Jo J., Hong H. H., Kim K. K., Park J. K., Cho S. J., et al. (2016). State-of-the-art housekeeping proteins for quantitative western blotting: revisiting the first draft of the human proteome. Proteomics 16 1863–1867. 10.1002/pmic.201500344 PubMed DOI

Leontieva O. V., Paszkiewicz G. M., Blagosklonny M. V. (2012). Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging. Aging 4 899–916. 10.18632/aging.100528 PubMed DOI PMC

Leroy C., Pierre K., Simpson I. A., Pellerin L., Vannucci S. J., Nehlig A. (2011). Temporal changes in mRNA expression of the brain nutrient transporters in the lithium-pilocarpine model of epilepsy in the immature and adult rat. Neurobiol. Dis. 43 588–597. 10.1016/j.nbd.2011.05.007 PubMed DOI PMC

Leroy C., Roch C., Koning E., Namer I. J., Nehlig A. (2003). In the lithium-pilocarpine model of epilepsy, brain lesions are not linked to changes in blood-brain barrier permeability: an autoradiographic study in adult and developing rats. Exp. Neurol. 182 361–372. 10.1016/S0014-4886(03)00122-5 PubMed DOI

Lowry O. H., Passoneau J. V. (1972). A Flexible System of Enzymatic Analysis. Amsterdam: Elsevier.

Malkov A., Ivanov A. I., Buldakova S., Waseem T., Popova I., Zilberter M., et al. (2018). Seizure-induced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis. Neurobiol. Dis. 116 28–38. 10.1016/j.nbd.2018.04.016 PubMed DOI

Malkov A., Ivanov A. I., Latyshkova A., Bregestovski P., Zilberter M., Zilberter Y. (2019). Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models. Ann. Neurol. 85 907–920. 10.1002/ana.25474 PubMed DOI

Martínez-Reyes I., Chandel N. S. (2020). Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11 1–11. 10.1038/s41467-019-13668-3 PubMed DOI PMC

Mazzuferi M., Kumar G., Van Eyll J., Danis B., Foerch P., Kaminski R. M. (2013). Nrf2 defense pathway: experimental evidence for its protective role in epilepsy. Ann. Neurol. 74 560–568. 10.1002/ana.23940 PubMed DOI

McDonald T. S., Carrasco-Pozo C., Hodson M. P., Borges K. (2017). Alterations in cytosolic and mitochondrial [U-13c]glucose metabolism in a chronic epilepsy mouse model. eNeuro 4: ENEURO.0341-16.2017. 10.1523/ENEURO.0341-16.2017 PubMed DOI PMC

Nuskova H., Mikesova J., Efimova I., Pecinova A., Pecina P., Drahota Z., et al. (2019). Biochemical thresholds for pathological presentation of ATP synthase deficiencies. Biochem. Biophys. Res. Commun. 521 1036–1041. 10.1016/j.bbrc.2019.11.033 PubMed DOI

Otáhal J., Folbergrová J., Kovacs R., Kunz W. S., Maggio N. (2014). Epileptic focus and alteration of metabolism. Int. Rev. Neurobiol. 114 209–243. 10.1016/B978-0-12-418693-4.00009-1 PubMed DOI

Parfenova H., Liu J., Hoover D. T., Fedinec A. L. (2020). Vasodilator effects of sulforaphane in cerebral circulation: a critical role of endogenously produced hydrogen sulfide and arteriolar smooth muscle K ATP and BK channels in the brain. J. Cerebr. Blood Flow Metab. 40 1987–1996. 10.1177/0271678X19878284 PubMed DOI PMC

Patel S., Fedinec A. L., Liu J., Weiss M. A., Pourcyrous M., Harsono M., et al. (2018). H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation. Am. J. Physiol. Heart Circ. Physiol. 315 H1759–H1764. 10.1152/ajpheart.00451.2018 PubMed DOI PMC

Pauletti A., Terrone G., Shekh-Ahmad T., Salamone A., Ravizza T., Rizzi M., et al. (2019). Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain 142 1885–1899. 10.1093/brain/awz130 PubMed DOI PMC

Paxinos G., Watson C. (1998). The Rat Brain in Stereotaxic Coordinates, 4th Edn. San Diego, CA: Academic Press.

Pereira de Vasconcelos A., Ferrandon A., Nehlig A. (2002). Local cerebral blood flow during lithium-pilocarpine seizures in the developing and adult rat: role of coupling between blood flow and metabolism in the genesis of neuronal damage. J. Cerebr. Blood Flow Metab. 22 196–205. 10.1097/00004647-200202000-00007 PubMed DOI

Pitkänen A., Lukasiuk K., Dudek F. E., Staley K. J. (2015). Epileptogenesis. Cold Spring Harb. Perspect. Med. 5:a022822. 10.1101/cshperspect.a022822 PubMed DOI PMC

Pumain R., Ahmed M. S., Kurcewicz I., Trottier S., Louvel J., Turak B., et al. (2008). Lability of GABAA receptor function in human partial epilepsy: possible relationship to hypometabolism. Epilepsia 49 87–90. 10.1111/j.1528-1167.2008.01845.x PubMed DOI

Ryan K., Backos D. S., Reigan P., Patel M. (2012). Post-translational oxidative modification and inactivation of mitochondrial complex I in epileptogenesis. J. Neurosci. 32 11250–11258. 10.1523/JNEUROSCI.0907-12.2012 PubMed DOI PMC

Samokhina E., Popova I., Malkov A., Ivanov A. I., Papadia D., Osypov A., et al. (2017). Chronic inhibition of brain glycolysis initiates epileptogenesis. J. Neurosci. Res. 95 2195–2206. 10.1002/jnr.24019 PubMed DOI

Sarikaya I. (2015). Review Article PET studies in epilepsy. Am. J. Nuclear Med. Mol. Imaging 5 416–430. PubMed PMC

Schauwecker P. E. (2012). Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus. Neurobiol. Dis. 45 297–304. 10.1016/j.nbd.2011.08.013 PubMed DOI PMC

Schiffer W. K., Mirrione M. M., Biegon A., Alexoff D. L., Patel V., Dewey S. L. (2006). Serial microPET measures of the metabolic reaction to a microdialysis probe implant. J. Neurosci. Methods 155 272–284. 10.1016/j.jneumeth.2006.01.027 PubMed DOI

Schönfeld P., Reiser G. (2013). Why does brain metabolism not favor burning of fatty acids to provide energy-Reflections on disadvantages of the use of free fatty acids as fuel for brain. J. Cerebr. Blood Flow Metab. 33 1493–1499. 10.1038/jcbfm.2013.128 PubMed DOI PMC

Shekh-Ahmad T., Eckel R., Dayalan Naidu S., Higgins M., Yamamoto M., DInkova-Kostova A. T., et al. (2018). KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain 141 1390–1403. 10.1093/brain/awy071 PubMed DOI

Svoboda J., Litvinec A., Kala D., Pošusta A., Vávrová L., Jiruška P., et al. (2019). Strain differences in intraluminal thread model of middle cerebral artery occlusion in rats. Physiol. Res. 68 37–48. 10.33549/physiolres.933958 PubMed DOI

Von Oertzen T. J. (2018). PET and ictal SPECT can be helpful for localizing epileptic foci. Curr. Opin. Neurol. 31 184–191. 10.1097/WCO.0000000000000527 PubMed DOI PMC

Waldbaum S., Patel M. (2010). Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy? J. Bioenerget. Biomembr. 42 449–455. 10.1007/s10863-010-9320-9 PubMed DOI PMC

Wang S. S. H., Shultz J. R., Burish M. J., Harrison K. H., Hof P. R., Towns L. C., et al. (2008). Functional trade-offs in white matter axonal scaling. J. Neurosci. 28 4047–4056. 10.1523/JNEUROSCI.5559-05.2008 PubMed DOI PMC

Wang W., Wu Y., Zhang G., Fang H., Wang H., Zang H., et al. (2014). Activation of Nrf2-ARE signal pathway protects the brain from damage induced by epileptic seizure. Brain Res. 1544 54–61. 10.1016/j.brainres.2013.12.004 PubMed DOI

Weaver D. F., Pohlmann-Eden B. (2013). Pharmacoresistant epilepsy: unmet needs in solving the puzzle(s). Epilepsia 54 80–85. 10.1111/epi.12191 PubMed DOI

Wiczk A., Hofman D., Konopa G., Herman-Antosiewicz A. (2012). Sulforaphane, a cruciferous vegetable-derived isothiocyanate, inhibits protein synthesis in human prostate cancer cells. Biochim. Biophys. Acta Mol. Cell Res. 1823 1295–1305. 10.1016/j.bbamcr.2012.05.020 PubMed DOI

Wong M. (2013). A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev. Neurother. 13 657–669. 10.1586/ern.13.48 PubMed DOI PMC

Yao R., Lecomte R., Crawford E. S. (2012). Small-animal PET: what is it, and why do we need it? J. Nuclear Med. Technol. 40 157–165. 10.2967/jnmt.111.098632 PubMed DOI

Zack M. M., Kobau R. (2017). National and state estimates of the numbers of adults and children with active epilepsy — United States, 2015. Morb. Mortal. Wkly. Rep. 66 821–825. 10.15585/mmwr.mm6631a1 PubMed DOI PMC

Zehendner C. M., Tsohataridis S., Luhmann H. J., Yang J. W. (2013). Developmental switch in neurovascular coupling in the immature rodent barrel cortex. PLoS One 8:e0080749. 10.1371/journal.pone.0080749 PubMed DOI PMC

Zhang F. (2017). Sulforaphane protects against brain diseases: roles of cytoprotective enzymes. Austin J. Cerebrovasc. Dis. Stroke 4 1–17. 10.26420/austinjcerebrovascdisstroke.2017.1054 PubMed DOI PMC

Zhang Y., Gilmour A., Ahn Y. H., de la Vega L., Dinkova-Kostova A. T. (2019). The isothiocyanate sulforaphane inhibits mTOR in an NRF2-independent manner. Phytomedicine 86:153062. 10.1016/j.phymed.2019.153062 PubMed DOI PMC

Epilepsy Research in the Institute of Physiology of the Czech Academy of Sciences in Prague

Protective Effect of Sulforaphane on Oxidative Stress and Mitochondrial Dysfunction Associated with Status Epilepticus in Immature Rats

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