RGD Reference Report - Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. - Rat Genome Database

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Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy.

Authors: Ravizza, T  Lucas, SM  Balosso, S  Bernardino, L  Ku, G  Noe, F  Malva, J  Randle, JC  Allan, S  Vezzani, A 
Citation: Ravizza T, etal., Epilepsia. 2006 Jul;47(7):1160-8.
RGD ID: 2315919
Pubmed: PMID:16886979   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1528-1167.2006.00590.x   (Journal Full-text)

PURPOSE: Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures. We previously found that intracerebral administration of interleukin-1 (IL-1)-beta has proconvulsant effects, whereas its endogenous receptor antagonist (IL-1Ra) mediates potent anticonvulsant actions in various models of limbic seizures. In this study, we investigated whether seizures can be effectively inhibited by blocking the brain production of IL-1beta, by using selective inhibitors of interleukin-converting enzyme (ICE/caspase-1) or through caspase-1 gene deletion. METHODS: Caspase-1 was selectively blocked by using pralnacasan or VX-765. IL-1beta release was induced in mouse organotypic hippocampal slice cultures by proinflammatory stimuli [lipopolysaccharide (LPS) + adenosine triphosphate (ATP)] and measured with enzyme-linked immunosorbent assay (ELISA). IL-1beta production during seizures was measured in the rat hippocampus by Western blot. Seizures were induced in freely moving mice and rats by intrahippocampal injection of kainic acid and recorded by EEG analysis. RESULTS: Caspase-1 inhibition reduced the release of IL-1beta in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 microg) or VX-765 (intraperitoneal, 25-200 mg/kg) to rats blocked seizure-induced production of IL-1beta in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration. Mice with caspase-1 gene deletion showed a 70% reduction in seizures and an approximate fourfold delay in their onset. CONCLUSIONS: Inhibition of caspase-1 represents an effective and novel anticonvulsive strategy, which acts by selectively reducing the brain availability of IL-1beta.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CASP1HumanExperimental Seizures treatmentISOCasp1 (Rattus norvegicus) RGD 
Casp1RatExperimental Seizures treatmentIMP  RGD 
Casp1MouseExperimental Seizures treatmentISOCasp1 (Rattus norvegicus) RGD 
IL1BHumanExperimental Seizures treatmentISOIl1b (Rattus norvegicus) RGD 
Il1bRatExperimental Seizures treatmentIEP  RGD 
Il1bMouseExperimental Seizures treatmentISOIl1b (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Casp1  (caspase 1)
Il1b  (interleukin 1 beta)

Genes (Mus musculus)
Casp1  (caspase 1)
Il1b  (interleukin 1 beta)

Genes (Homo sapiens)
CASP1  (caspase 1)
IL1B  (interleukin 1 beta)


Additional Information