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: 5.05). 03/2011; 8(2):304-15. DOI: 10.1007/s13311-011-0039-z
Source: PubMed


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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    • "The antibody immunoprecipitates polypeptide chains of 160 and 95 kDa (Robinson et al., 1986). Antibodies to CD11b have been used to immunostain microglia in the brain (Jeong et al., 2010; Maroso et al., 2011; Fuentes- Santamaria et al., 2013). CD68 (Serotech #MCA341GA). "
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    • "Data were presented as mean ± SEM. Zhang et al. | 7 We used a highly potent and selective caspase-1 inhibitor VX-765 to reduce production of IL-1β by blocking the NLRP3 inflammasome signaling (Maroso et al., 2011). Our study results confirmed that expression and activation of the NLRP3 inflammasome were effectively inhibited by the inflammasome inhibitor VX-765 (Figure 3). "
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