title: Neuroprotection of co-activation of GABA receptors by preventing caspase-3 denitrosylation in KA-induced seizures.
abstract: Previous studies have demonstrated that kainic acid (KA)-induced seizures can cause the enhancement of excitation and lead to neuronal death in rat hippocampus. Co-activation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module induced by KA in epileptic rat hippocampal CA1 and CA3 regions. Caspase-3 is a cysteine protease located in both the cytoplasm and mitochondrial intermembrane space that is a central effector of many apoptotic pathways. We designed experiments to elucidate the underlying molecular mechanisms of procaspase-3 activation and neuroprotection of co-activation of GABA receptors against neuronal death induced by KA. In this study, we show that co-activation of GABA receptors can attenuate the Fas/FasL apoptotic signaling pathway and inhibit the increased of thioredoxin reductase activity induced by KA, subsequently inhibit the activation of procaspase-3 by diminishing the denitrosylation of its active-site thiol and decreasing the cleavage of the caspase-3 zymogen to its active subunits. These results indicate that co-activation of GABA receptors results in neuroprotection by preventing caspase-3 denitrosylation in KA-induced seizure of rats.
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation and Research Center of Biochemistry and Molecular Biochemistry, Xuzhou Medical College, Xuzhou 221002, China.
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Wei
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001418:Baclofen / Q000008:administration & dosage / Q000627:therapeutic use*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D003292:Convulsants / Q000633:toxicity*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D009118:Muscimol / Q000008:administration & dosage / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity*; D015538:Nitrosation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D003292:Convulsants; D053222:Fas Ligand Protein; C491898:Fas protein, rat; C505662:Faslg protein, rat; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018079:Receptors, GABA; D013438:Sulfhydryl Compounds; D019014:fas Receptor; D009118:Muscimol; D013880:Thioredoxin-Disulfide Reductase; C505410:Casp3 protein, rat; D053148:Caspase 3; D001418:Baclofen; D007608:Kainic Acid