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, Sep 01, 2015
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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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    ABSTRACT: Exposure to loud, prolonged sounds (acoustic trauma, AT) leads to the death of both inner and outer hair cells (IHCs and OHCs), death of neurons of the spiral ganglion and degeneration of the auditory nerve. The auditory nerve (8cn) projects to the three subdivisions of the cochlear nuclei (CN), the dorsal cochlear nucleus (DC) and the anterior (VCA) and posterior (VCP) subdivisions of the ventral cochlear nucleus. There is both anatomical and physiological evidence for plastic reorganization in the denervated CN after AT. Anatomical findings show axonal sprouting and synaptogenesis; physiologically there is an increase in spontaneous activity suggesting reorganization of circuitry. The mechanisms underlying this plasticity are not understood. Recent data suggest that activated microglia may have a role in facilitating plastic reorganization in addition to removing trauma-induced debris. In order to investigate the roles of activated microglia in the CN subsequent to acoustic trauma we exposed animals to bilateral noise sufficient to cause massive hair cell death. We studied four groups of animals at different survival times: 30 days, 60 days, 6 months and 9 months. We used silver staining to examine the time course and pattern of auditory nerve degeneration, and immunohistochemistry to label activated microglia in the denervated CN. We found both degenerating auditory nerve fibers and activated microglia in the CN at 30 and 60 days and 6 months after AT. There was close geographic overlap between the degenerating fibers and activated microglia, consistent with a scavenger role for activated microglia. At the longest survival time, there were still silver-stained fibers but very little staining of activated microglia in overlapping regions. There were, however, activated microglia in the surrounding brainstem and cerebellar white matter. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 303. DOI:10.1016/j.neuroscience.2015.07.004 · 3.33 Impact Factor
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    • "In addition, intravenous immunoglobulin (IVIG) can suppress seizures in some types of intractable epilepsy, an effect that may be partially mediated through a reduction in cytokines and a suppression of astrocyte activation [15, 16]. These drugs are also able to confer protection against seizures in mice with some types of epilepsy that are resistant to conventional AEDs [17]. Combined with antiglial functions of conventional AEDs described above, anti-inflammatory medication could be a new promising treatment for refractory epilepsy. "
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    ABSTRACT: Epilepsy is one of the most common chronic brain disorders worldwide, affecting 1% of people across different ages and backgrounds. Epilepsy is defined as the sporadic occurrence of spontaneous recurrent seizures. Accumulating preclinical and clinical evidence suggest that there is a positive feedback cycle between epileptogenesis and brain inflammation. Epileptic seizures increase key inflammatory mediators, which in turn cause secondary damage to the brain and increase the likelihood of recurrent seizures. Cytokines and prostaglandins are well-known inflammatory mediators in the brain, and their biosynthesis is enhanced following seizures. Such inflammatory mediators could be therapeutic targets for the development of new antiepileptic drugs. In this review, we discuss the roles of inflammatory mediators in epileptogenesis.
    Mediators of Inflammation 08/2014; 2014(2):901902. DOI:10.1155/2014/901902 · 3.24 Impact Factor
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    • "A previous study found that in control rats there is only slight expression of IL-1β in the CA3 region of the hippocampus;16 however, a different study demonstrated prominent IL-1β expression in scattered neurons of the dentate gyrus and less expression in the neurons in CA3 and CA1.9 Other studies have failed to detect any IL-1β immunoreactivity at all.20,22 In the present study, IL-1β was weakly expressed in pyramidal neurons in CA3, showing that IL-1β is not highly expressed in the hippocampus under normal circumstances in non-epileptic animals. "
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    ABSTRACT: BACKGROUND The time course of cytokine dynamics after seizure remains controversial. Here we evaluated the changes in the levels and sites of interleukin (IL)-1β expression over time in the hippocampus after seizure. METHODS Status epilepticus (SE) was induced in adult Wistar rats by means of intraperitoneal injection of kainic acid (KA). Subsequently, the time courses of cellular localization and IL-1β concentration in the hippocampus were evaluated by means of immunohistochemical and quantitative assays. RESULTS On day 1 after SE, CA3 pyramidal cells showed degeneration and increased IL-1β expression. In the chronic phase (>7 days after SE), glial fibrillary acidic protein (GFAP)—positive reactive astrocytes—appeared in CA1 and became IL-1β immunoreactive. Their IL-1β immunoreactivity increased in proportion to the progressive hypertrophy of astrocytes that led to gliosis. Quantitative analysis showed that hippocampal IL-1β concentration progressively increased during the acute and chronic phases. CONCLUSION IL-1β affects the hippocampus after SE. In the acute phase, the main cells expressing IL-1β were CA3 pyramidal cells. In the chronic phase, the main cells expressing IL-1β were reactive astrocytes in CA1.
    08/2014; 5:25-32. DOI:10.4137/JCM.S13738
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