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.
Copyright 2001 Academic Press.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amygdala / metabolism
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Amygdala / pathology*
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Animals
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Apoptosis / physiology*
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / analysis
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Carrier Proteins / biosynthesis
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Carrier Proteins / metabolism*
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Caspase 3
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Caspase 8
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Caspase 9
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Caspase Inhibitors
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Caspases / analysis
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Caspases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Fragmentation / physiology
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Electroencephalography
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Enzyme Inhibitors / pharmacology
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Epilepsy / chemically induced
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Epilepsy / pathology*
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Fas-Associated Death Domain Protein
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Glioma
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Immunohistochemistry
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In Situ Nick-End Labeling
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Male
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Neurons / enzymology
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Neurons / pathology*
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Oligopeptides / pharmacology
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Protein Biosynthesis
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Proteins / analysis
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Rats
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Rats, Sprague-Dawley
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / analysis
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor, Member 25
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Staurosporine / pharmacology
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TNF Receptor-Associated Factor 1
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Tumor Cells, Cultured
Substances
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Adaptor Proteins, Signal Transducing
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BH3 Interacting Domain Death Agonist Protein
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Bid protein, rat
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Carrier Proteins
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Enzyme Inhibitors
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FADD protein, human
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Fadd protein, rat
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Fas-Associated Death Domain Protein
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Oligopeptides
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Proteins
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Member 25
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TNF Receptor-Associated Factor 1
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TNFRSF10A protein, human
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TNFRSF25 protein, human
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benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Casp3 protein, rat
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Casp8 protein, rat
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Casp9 protein, rat
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases
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Staurosporine