Abstract
An enhanced production of IL-1beta in glia is a typical feature of epileptogenic tissue in experimental models and in human drug-refractory epilepsy. We show here that the selective inhibition of Interleukin Converting Enzyme (ICE), which cleaves the biologically active form of IL-1beta using VX-765, blocks kindling development in rats by preventing IL-1beta increase in forebrain astrocytes, without interfering with glia activation. The average afterdischarge duration was not altered significantly by VX-765. Up to 24 h after kindling completion and drug washout, kindled seizures could not be evoked in treated rats. VX-765 did not affect seizures or afterdischarge duration in fully kindled rats. These data indicate an antiepileptogenic effect mediated by ICE inhibition and suggest that specific anti-IL-1beta pharmacological strategies can be envisaged to interfere with epileptogenic mechanisms.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Aminobenzoic Acid / pharmacology
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4-Aminobenzoic Acid / therapeutic use
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Animals
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Anticonvulsants / pharmacology
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Anticonvulsants / therapeutic use
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Astrocytes / drug effects
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Astrocytes / metabolism*
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Caspase 1 / metabolism*
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Caspase Inhibitors
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Dipeptides / pharmacology
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Dipeptides / therapeutic use
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Epilepsy / drug therapy
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Epilepsy / physiopathology*
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / metabolism*
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Kindling, Neurologic / drug effects
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Kindling, Neurologic / metabolism*
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Male
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Prosencephalon / drug effects
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Prosencephalon / physiopathology*
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Rats
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Rats, Sprague-Dawley
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para-Aminobenzoates
Substances
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Anticonvulsants
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Caspase Inhibitors
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Dipeptides
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Enzyme Inhibitors
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Interleukin-1beta
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para-Aminobenzoates
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belnacasan
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Caspase 1
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4-Aminobenzoic Acid