Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

被引:237
作者
Maroso, Mattia [1 ]
Balosso, Silvia [1 ]
Ravizza, Teresa [1 ]
Iori, Valentina [1 ]
Wright, Christopher Ian [2 ]
French, Jacqueline [3 ]
Vezzani, Annamaria [1 ]
机构
[1] Mario Negri Inst Pharmacol Res, Dept Neurosci, I-20156 Milan, Italy
[2] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA
[3] NYU, Comprehens Epilepsy Ctr, New York, NY 10016 USA
关键词
Astrocytes; anticonvulsant drug; inflammation; IL-1; beta; temporal lobe epilepsy; TEMPORAL-LOBE EPILEPSY; GRANULE CELL DISPERSION; BOTULINUM NEUROTOXIN-E; TUMOR-NECROSIS-FACTOR; MOUSE MODEL; HIPPOCAMPAL SCLEROSIS; RAT HIPPOCAMPUS; KAINIC ACID; INFLAMMATORY CYTOKINES; RECEPTOR ANTAGONISTS;
D O I
10.1007/s13311-011-0039-z
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Experimental evidence and clinical observations indicate that brain inflammation is an important factor in epilepsy. In particular, induction of interleukin-converting enzyme (ICE)/caspase-1 and activation of interleukin (IL)-1 beta/IL-1 receptor type 1 axis both occur in human epilepsy, and contribute to experimentally induced acute seizures. In this study, the anticonvulsant activity of VX-765 (a selective ICE/caspase-1 inhibitor) was examined in a mouse model of chronic epilepsy with spontaneous recurrent epileptic activity refractory to some common anticonvulsant drugs. Moreover, the effects of this drug were studied in one acute model of seizures in mice, previously shown to involve activation of ICE/caspase-1. Quantitative analysis of electroencephalogram activity was done in mice exposed to acute seizures or those developing chronic epileptic activity after status epilepticus to assess the anticonvulsant effects of systemic administration of VX-765. Histological and immunohistochemical analysis of brain tissue was carried out at the end of pharmacological experiments in epileptic mice to evaluate neuropathology, glia activation and IL-1 beta expression, and the effect of treatment. Repeated systemic administration of VX-765 significantly reduced chronic epileptic activity in mice in a dose-dependent fashion (12.5-200 mg/kg). This effect was observed at doses a parts per thousand yenaEuro parts per thousand 50 mg/kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1 beta synthesis in activated astrocytes. The same dose regimen of VX-765 also reduced acute seizures in mice and delayed their onset time. These results support a new target system for anticonvulsant pharmacological intervention to control epileptic activity that does not respond to some common anticonvulsant drugs.
引用
收藏
页码:304 / 315
页数:12
相关论文
共 55 条
[1]   Botulinum neurotoxin E (BoNT/E) reduces CA1 neuron loss and granule cell dispersion, with no effects on chronic seizures, in a mouse model of temporal lobe epilepsy [J].
Antonucci, Flavia ;
Di Garbo, Angelo ;
Novelli, Elena ;
Manno, Ilaria ;
Sartucci, Ferdinando ;
Bozzi, Yuri ;
Caleo, Matteo .
EXPERIMENTAL NEUROLOGY, 2008, 210 (02) :388-401
[2]   Tumor necrosis factor-α inhibits seizures in mice via p75 receptors [J].
Balosso, S ;
Ravizza, T ;
Perego, C ;
Peschon, J ;
Campbell, IL ;
De Simoni, MG ;
Vezzani, A .
ANNALS OF NEUROLOGY, 2005, 57 (06) :804-812
[3]   A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β [J].
Balosso, Silvia ;
Maroso, Mattia ;
Sanchez-Alavez, Manuel ;
Ravizza, Teresa ;
Frasca, Angelisa ;
Bartfai, Tamas ;
Vezzani, Annamaria .
BRAIN, 2008, 131 :3256-3265
[4]   Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury:: a crucial role of P2X7 receptor-mediated IL-1β release [J].
Bernardino, Liliana ;
Balosso, Silvia ;
Ravizza, Teresa ;
Marchi, Nicola ;
Ku, George ;
Randle, John C. ;
Malva, Joao O. ;
Vezzani, Annamaria .
JOURNAL OF NEUROCHEMISTRY, 2008, 106 (01) :271-280
[5]   CXCR4-activated astrocyte glutamate release via TNFa: amplification by microglia triggers neurotoxicity [J].
Bezzi, P ;
Domercq, M ;
Brambilla, L ;
Galli, R ;
Schols, D ;
De Clercq, E ;
Vescovi, A ;
Bagetta, G ;
Kollias, G ;
Meldolesi, J ;
Volterra, A .
NATURE NEUROSCIENCE, 2001, 4 (07) :702-710
[6]   Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex [J].
Boer, K. ;
Jansen, F. ;
Nellist, M. ;
Redeker, S. ;
van den Ouweland, A. M. W. ;
Spliet, W. G. M. ;
van Nieuwenhuizen, O. ;
Troost, D. ;
Crino, P. B. ;
Aronica, E. .
EPILEPSY RESEARCH, 2008, 78 (01) :7-21
[7]   Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: Electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy [J].
Bouilleret, V ;
Ridoux, V ;
Depaulis, A ;
Marescaux, C ;
Nehlig, A ;
La Salle, GL .
NEUROSCIENCE, 1999, 89 (03) :717-729
[8]   CYTOKINES, GLUCOCORTICOIDS AND NEUROENDOCRINE FUNCTION [J].
BUCKINGHAM, JC ;
LOXLEY, HD ;
TAYLOR, AD ;
FLOWER, RJ .
PHARMACOLOGICAL RESEARCH, 1994, 30 (01) :35-42
[9]  
*CLINICALTRIALS GO, 2010, STUD VX 765 SUBJ TRE
[10]   Inflammatory caspases: Targets for novel therapies [J].
Cornelis, Sigrid ;
Kersse, Kristof ;
Festjens, Nele ;
Lamkanfi, Mohamed ;
Vandenabeele, Peter .
CURRENT PHARMACEUTICAL DESIGN, 2007, 13 (04) :367-385