title: Sulforaphane is anticonvulsant and improves mitochondrial function.
abstract: The nuclear factor erythroid 2-related factor 2 pathway (Nrf2) has been previously identified to protect the brain against various impacts. Here, we investigated the effect of the Nrf2 activator sulforaphane in various seizure models and hippocampal mitochondrial bioenergetics. We found that daily injections of sulforaphane for 5 days elevated the seizure thresholds to 6 Hz stimulation and fluorothyl-, but not pentylenetetrazole-induced tonic seizures and protected mice against pilocarpine-induced status epilepticus (SE). Also, sulforaphane increased the antioxidant defences within hippocampal formations and blood plasma. In addition, sulforaphane treatment reduced the extent of hippocampal lipid peroxidation 24 h post-SE and protected hippocampal mitochondria against SE-induced reduction in state 2 and uncoupler-stimulated state 3 respiration. SE-mediated partial loss of rotenone-sensitive and complex II-driven respiration was reduced, consistent with the enhanced activities of complexes I and II in sulforaphane-treated SE mice. In mitochondria isolated from both no SE and SE mice, sulforaphane increased state 3 respiration and respiration linked to ATP synthesis, which may contribute to its anticonvulsant and antioxidant effects by providing more ATP for cellular vital and protective functions. However, sulforaphane did not prevent SE-induced hippocampal cell death. In conclusion, sulforaphane and/or Nrf2 activation are viable anticonvulsant strategies, which are antioxidant and enhance mitochondrial function, especially the ability to produce ATP. Sulforaphane was anticonvulsant in two acute mouse models of epilepsy and protected mice against pilocarpine-induced status epilepticus (SE). We also found antioxidant effects of sulforaphane in mouse plasma and hippocampal formations, exhibited by increased catalase and superoxide dismutase (SOD) activity, as well as increased abilities of hippocampal mitochondria to produce ATP. These effects likely underlie sulforaphane's anticonvulsant mechanisms of action.
authors.affiliation: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia.|Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Carrasco-Pozo
authors.affiliation: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Kah Ni
authors.initials: KN
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: Borges
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D005481:Flurothyl / Q000633:toxicity; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure*; D017879:Isothiocyanates / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010433:Pentylenetetrazole / Q000633:toxicity; D010862:Pilocarpine / Q000633:toxicity; D013454:Sulfoxides; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D017879:Isothiocyanates; D013454:Sulfoxides; D010862:Pilocarpine; D008315:Malondialdehyde; D005481:Flurothyl; D013482:Superoxide Dismutase; D042967:Electron Transport Complex I; C016766:sulforaphane; D010433:Pentylenetetrazole
keywords: Nrf2; epilepsy; mitochondrial respiration; pilocarpine; seizure; sulforaphane