Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production.
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.
Ravizza
Teresa
T
Department of Neuroscience, Laboratory of Experimental Neurology, Mario Negri Institute for Pharmacological Research, Milano, Italy.
Noé
Francesco
F
Zardoni
Daniela
D
Vaghi
Valentina
V
Sifringer
Marco
M
Vezzani
Annamaria
A
D010129:4-Aminobenzoic Acid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016548:Prosencephalon / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D062366:para-Aminobenzoates
D000927:Anticonvulsants; D061945:Caspase Inhibitors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D062366:para-Aminobenzoates; C520022:belnacasan; D020170:Caspase 1; D010129:4-Aminobenzoic Acid