The role of inflammation in epileptogenesis

Laboratory Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via G. La Masa 19, 20156 Milano, Italy.
Neuropharmacology (Impact Factor: 5.11). 04/2012; 69. DOI: 10.1016/j.neuropharm.2012.04.004
Source: PubMed


One compelling challenge in the therapy of epilepsy is to develop anti-epileptogenic drugs with an impact on the disease progression. The search for novel targets has focused recently on brain inflammation since this phenomenon appears to be an integral part of the diseased hyperexcitable brain tissue from which spontaneous and recurrent seizures originate. Although the contribution of specific proinflammatory pathways to the mechanism of ictogenesis in epileptic tissue has been demonstrated in experimental models, the role of these pathways in epileptogenesis is still under evaluation. We review the evidence conceptually supporting the involvement of brain inflammation and the associated blood-brain barrier damage in epileptogenesis, and describe the available pharmacological evidence where post-injury intervention with anti-inflammatory drugs has been attempted. Our review will focus on three main inflammatory pathways, namely the IL-1 receptor/Toll-like receptor signaling, COX-2 and the TGF-β signaling. The mechanisms underlying neuronal-glia network dysfunctions induced by brain inflammation are also discussed, highlighting novel neuromodulatory effects of classical inflammatory mediators such as cytokines and prostaglandins. The increase in knowledge about a role of inflammation in disease progression, may prompt the use of specific anti-inflammatory drugs for developing disease-modifying treatments. This article is part of a Special issue entitled 'Epilepsy'.

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Available from: Alon Friedman, Mar 16, 2014
    • "Third, although we were unable to confirm the previously reported association with therapeutic measures like the use of anesthetics or the induction of burst suppression, outcome after RSE was clearly influenced by treatment and complications in our cohort. On the one hand, elevated CRP levels on admission and development of sepsis during the hospital stay predisposed poor outcome, a finding which might reflect that epileptic activity per se leads to systemic inflammatory reactions[28], or, alternatively, underscores the impact of certain pro-inflammatory pathways on neuronal excitability and therefore seizure refractoriness[29]. On the other hand, duration of RSE was strongly associated with overall long-term outcome, while it did not show significant impact on in-hospital mortality. "
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    ABSTRACT: The aim of the study was to identify factors influencing long-term outcome and to evaluate the prognostic power of the Status Epilepticus Severity Score (STESS) in refractory status epilepticus (RSE). We retrospectively extracted data on baseline characteristics, RSE details, and hospital course including complications from all patients treated for RSE in our institution between January 2001 and January 2013. Functional outcome was assessed using the modified Rankin Scale (mRS) and was defined as good when either RSE did not lead to functional decline or when the resulting mRS score was 2 or below. Seventy-one episodes in 65 patients were analyzed. The median follow-up time was 12 weeks (IQR 6-35), two patients were lost to follow-up. Poor functional long-term outcome was observed in 42/69 (60.9 %) episodes. In-hospital mortality occurred in 13/71 (18.3 %) episodes. Multivariable analysis revealed that STESS ≥ 3, longer RSE duration, and sepsis were independently related to poor functional long-term outcome. Receiver operating characteristics (ROC) curve analyses confirmed the cut-off dichotomization into STESS ≥ 3 and STESS < 3 for optimal discrimination between good and poor outcome (AUC = 0.671, p = 0.002, YI = 0.368, NPV = 0.607, PPV = 0.756) and revealed an RSE duration of 10 days as a significant cut-off point associated with outcome (AUC = 0.712, p = 0.012, YI = 0.310; NPV = 0.545, PPV = 0.750). In conclusion, STESS and RSE duration represent relevant scores and parameters impacting long-term outcome after RSE. A shorter RSE duration is associated with better outcome and, therefore, rapid and adequate treatment for seizure termination should be enforced.
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    • "Proinflammatory molecules, such as cytokines, chemokines, and prostaglandins, have an increasingly recognized " neuromodulatory " role mediated either by the direct activation of their cognate receptors in neurons or, indirectly, by autocrine receptor stimulation in glia leading to alterations of glial cell physiology, which, in turn, perturb glioneuronal communications (Aronica et al. 2012b;Devinsky et al. 2013). IL-1b, TNF-a, and IL-6 and prostaglandins, such as PGE2 and PGF2a, modify voltage-and receptor-gated ion channel function via rapid activation of posttranslational mechanisms in neurons involving protein kinases (Viviani et al. 2007;Kulkarni and Dhir 2009;Vezzani et al. 2013b). Cytokines also promote changes in neuronal glutamate (N-methyl-D-aspartate[NMDA]and AMPA) and g-aminobutyric acid (GABA) A receptor expression, and alter their molecular subunit composition by activating protein kinases (Stellwagen et al. 2005;Balosso et al. 2009). "
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    ABSTRACT: This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.
    Full-text · Article · Dec 2015 · Cold Spring Harbor Perspectives in Medicine
    • "a substantial role in the seizure process, particularly IL-1, TNF-a and IL-6 (Galic et al., 2012; Li et al., 2011; Vezzani et al., 2013). "
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    ABSTRACT: TsTX-I, isolated from Tityus serrulatus scorpion venom, causes epileptic-like discharges when injected into the central nervous system. The involvement of excitatory amino acids and cytokines in this activity was investigated. Our results have demonstrated that TsTX-I increases the release of IFN-γ but does not alter the intracerebral concentration of the excitatory amino acids in rats. Thus, this cytokine seems to be more important in the convulsive process than glutamate. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Toxicon
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