Caspase-2 activation is redundant during seizure-induced neuronal death.
Seizure-induced neuronal death may be under the control of the caspase family of cell death proteases. We examined the role of caspase-2 in a model of focally evoked limbic seizures with continuous EEG recording. Seizures were elicited by microinjection of kainic acid into the amygdala of the rat and terminated after 40 min by diazepam. Caspase-2 was constitutively present in brain, mostly within neurons, and was detected in both cytoplasm and nucleus. Cleaved caspase-2 (12 kDa) was detected immediately following seizure termination within injured ipsilateral hippocampus, contiguous with increased Val-Asp-Val-Ala-Asp (VDVADase) activity, a putative measure of activated caspase-2. Expression of receptor interacting protein (RIP)-associated Ich-1-homologous protein with death domain (RAIDD) was increased following seizures, whereas expression of RIP and tumor necrosis factor receptor associated protein with death domain (TRADD), other components thought to be linked to the caspase-2 activation and signaling mechanism, were unchanged. Intracerebroventricular administration of z-VDVAD-fluoromethyl ketone blocked seizure-induced caspase-2 activity but did not alter caspase-8 activity and failed to affect DNA fragmentation or neuronal death. These data support activation of caspase-2 following seizures but suggest that parallel caspase pathways may circumvent deficits in caspase-2 function to complete the cell death process.
Henshall
D C
DC
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA. dehnsall@DowNeurobiology.org
Skradski
S L
SL
Bonislawski
D P
DP
Lan
J Q
JQ
Simon
R P
RP
D000679:Amygdala / Q000187:drug effects; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology / Q000648:ultrastructure; D053143:Caspase 2; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D053938:DNA Fragmentation; D003975:Diazepam / Q000494:pharmacology; D004569:Electroencephalography; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000008:administration & dosage; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053143:Caspase 2; D020169:Caspases; D003975:Diazepam; D007608:Kainic Acid