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Neurobiol Dis. 2001 Aug;8(4):568-80.

Cleavage of bid may amplify caspase-8-induced neuronal death following focally evoked limbic seizures.

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1
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA. dhenshall@DowNeurobiology.org

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.

PMID:
11493022
DOI:
10.1006/nbdi.2001.0415
[Indexed for MEDLINE]

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