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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Available from: Valentina Iori, Sep 29, 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 · 3.36 Impact Factor
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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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    ABSTRACT: Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1β (IL-1β). The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions. To explore role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress (CMS). Mice subjected to CMS for 4 weeks had significantly higher serum corticosterone levels, serum IL-1β levels and hippocampal active IL-1β protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of CMS exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and ASC. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of IL-1β protein, and significantly moderated the depressive-like behaviors induced by CMS. These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(8). DOI:10.1093/ijnp/pyv006 · 4.01 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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