Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production.

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.

• Authors: Teresa Ravizza, Francesco Noé, Daniela Zardoni, Valentina Vaghi, Marco Sifringer, Annamaria Vezzani
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 31 Issue 3 Pg. 327-33 (Sep 2008) ISSN: 1095-953X [Electronic] United States
• PMID: 18632279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Caspase Inhibitors
• Dipeptides
• Enzyme Inhibitors
• Interleukin-1beta
• para-Aminobenzoates
• belnacasan
• Caspase 1
• 4-Aminobenzoic Acid

Topics

• 4-Aminobenzoic Acid (pharmacology, therapeutic use)
• Animals
• Anticonvulsants (pharmacology, therapeutic use)
• Astrocytes (drug effects, metabolism)
• Caspase 1 (metabolism)
• Caspase Inhibitors
• Dipeptides (pharmacology, therapeutic use)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Epilepsy (drug therapy, physiopathology)
• Interleukin-1beta (biosynthesis, metabolism)
• Kindling, Neurologic (drug effects, metabolism)
• Male
• Prosencephalon (drug effects, physiopathology)
• Rats
• Rats, Sprague-Dawley
• para-Aminobenzoates