title: Cleavage of bid may amplify caspase-8-induced neuronal death following focally evoked limbic seizures.
abstract: The mechanism by which seizures induce neuronal death is not completely understood. Caspase-8 is a key initiator of apoptosis via extrinsic, death receptor-mediated pathways; we therefore investigated its role in mediating seizure-induced neuronal death evoked by unilateral kainic acid injection into the amygdala of the rat, terminated after 40 min by diazepam. We demonstrate that cleaved (p18) caspase-8 was detectable immediately following seizure termination coincident with an increase in cleavage of the substrate Ile-Glu-Thr-Asp (IETD)-p-nitroanilide and the appearance of cleaved (p15) Bid. Expression of Fas and FADD, components of death receptor signaling, was increased following seizures. In vivo intracerebroventricular z-IETD-fluoromethyl ketone administration significantly reduced seizure-induced activities of caspases 8, 9, and 3 as well as reducing Bid and caspase-9 cleavage, cytochrome c release, DNA fragmentation, and neuronal death. These data suggest that intervention in caspase-8 and/or death receptor signaling may confer protection on the brain from the injurious effects of seizures.
authors.affiliation: Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA. dhenshall@DowNeurobiology.org
authors.forename: D C
authors.initials: DC
authors.lastname: Henshall
authors.forename: D P
authors.initials: DP
authors.lastname: Bonislawski
authors.forename: S L
authors.initials: SL
authors.lastname: Skradski
authors.forename: J Q
authors.initials: JQ
authors.lastname: Lan
authors.forename: R
authors.initials: R
authors.lastname: Meller
authors.forename: R P
authors.initials: RP
authors.lastname: Simon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000679:Amygdala / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000502:physiology; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology*; D053200:Fas-Associated Death Domain Protein; D005910:Glioma; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000096:biosynthesis; D053219:Receptors, Tumor Necrosis Factor, Member 25; D019311:Staurosporine / Q000494:pharmacology; D047990:TNF Receptor-Associated Factor 1; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; C505533:FADD protein, human; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D009842:Oligopeptides; D011506:Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047990:TNF Receptor-Associated Factor 1; C105190:TNFRSF10A protein, human; C506033:TNFRSF25 protein, human; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine