Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice.

Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy.
Journal of the American Society for Experimental NeuroTherapeutics (Impact Factor: 3.88). 03/2011; 8(2):304-15. DOI: 10.1007/s13311-011-0039-z
Source: PubMed

ABSTRACT 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)-1β/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-1β 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 ≥ 50 mg/kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1β 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.

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Available from: Valentina Iori, Jul 09, 2015
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    • "For example, new opportunities to prevent epilepsy may exist in situations where genetic testing could identify subjects at risk, for example, childhood absence epilepsy (Blumenfeld et al., 2008). Similarly new opportunities to prevent symptomatic, immune-mediated epilepsy with antiinflammatory or immunologic intervention (Dalmau et al., 2011; Maroso et al., 2011) may be just over the horizon. "
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    • "IL-1β; Sha et al., 2008) enables the recruitment of both receptors which appears to be required for promoting tissue inflammation (Rauvala and Rouhiainen, 2010). Notably, IL-1β is also induced in seizure models and in human mTLE (Maroso et al., 2011; Ravizza et al., 2008; Vezzani et al., 2011). "
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