Elsevier

Neuropharmacology

Volume 69, June 2013, Pages 16-24
Neuropharmacology

Invited review
The role of inflammation in epileptogenesis

https://doi.org/10.1016/j.neuropharm.2012.04.004Get rights and content

Abstract

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 the Special Issue entitled ‘New Targets and Approaches to the Treatment of Epilepsy’.

Introduction

In the last decade, evidence from clinical and experimental studies indicates that brain inflammation is an intrinsic feature of the hyperexcitable pathologic brain tissue in pharmacoresistant epilepsies of differing etiology (Vezzani et al., 2011a). Moreover, pharmacological studies in seizure models, and the assessment of seizure susceptibility in genetically modified mice with perturbed inflammatory signaling, demonstrate that brain inflammation is not a mere epiphenomenon of the pathologic tissue. Rather, brain inflammation contributes significantly to determine seizure threshold in susceptible brain regions, thus playing a role in seizure precipitation and their recurrence (Dubé et al., 2005; Kulkarni and Dhir, 2009; Riazi et al., 2010; Vezzani et al., 2011a, 2011c). Various in vitro and in vivo findings also suggest that specific sets of inflammatory molecules and their cognate receptors, when expressed in a permissive tissue environment, can mediate neuronal cell loss and contribute to the associated molecular and synaptic plasticity. These effects are shared by molecules acting as endogenous activators of the IL-1 Receptor/Toll-like receptor (IL-1R/TLR) or the Transforming Growth Factor (TGF)-β signaling, and by the products of the COX-2 pathway activation. More limited information is available on the physiopathological effects of other molecules of the inflammatory cascade that are upregulated in epileptic tissue, e.g., proinflammatory cytokines such as IL-6 and TNF-α, the tissue plasminogen activator, the membrane attack complex of the complement system, and the vasoactive endothelial growth factor (VEGF) (Croll et al., 2004; Ravizza et al., 2010).

Inflammatory processes are not only present in chronic epileptic brain but some of these pathways are also upregulated following an epileptogenic injury, and they often persist during the latent phase that precedes spontaneous recurrent seizures. This evidence has generated the testable hypothesis that brain inflammation, in addition to its established contribution to ictogenesis, may play a role in the development of the epileptogenic process. Studies related to the role of brain inflammation in epileptogenesis are still in their infancy, however there is available pharmacological evidence to support this role (Ravizza et al., 2011). One set of evidence also shows long-term increase in brain excitability in mice overexpressing cytokines in astroglia (Akassoglou et al., 1997; Campbell et al., 1993; Stalder et al., 1998), or in rodent brain after the induction of an inflammatory challenge, particularly if this event occurs during the early post-natal life (Riazi et al., 2010).

We describe here some of the experimental evidence that conceptually supports a role of brain inflammation in epileptogenesis by focusing on three main pathways, namely the Interleukin (IL)-1 receptor (R)/Toll-like receptor (TLR), Transforming Growth Factor (TGF)-β and Cyclooxygenase-2 (COX-2) signaling (Fig. 1). We will also present the pharmacological data obtained by targeting these systems in epileptogenesis models. Finally, we will address the usefulness of biomarkers of brain inflammation for prognostic and therapeutic purposes in symptomatic epilepsies, and will discuss the possibility that anti-inflammatory post-injury intervention may be of value for delaying or arresting the epileptic process.

Section snippets

Tissue inflammation and outcome determinants

Inflammation is regarded as an homeostatic mechanism induced in tissue by infection or injury in order to remove the specific pathogen or for tissue repair. It consists of the induction of an array of inflammatory molecules, classically initiated by the activation of innate immunity mechanisms. In some circumstances, inflammation can become detrimental for tissue resulting in cell dysfunction or death. The pathologic outcome of tissue inflammation has been well documented in autoinflammatory

Role of inflammation in altered neuronal excitability

Although cytokines and downstream mediators of the inflammatory cascade are considered as an integral part of innate and adaptive immunity activation in the periphery, it is now clear that these inflammatory molecules can also subserve non-conventional neuromodulatory functions in CNS by acting directly or indirectly on neurons, and affecting their excitability threshold at cellular and network levels.

Inflammation, cell loss, neuroplasticity

Many of the mediators of brain inflammation are not simply malicious, but carry out important physiological functions in non-pathological conditions. Neural networks in the healthy adult brain are being continuously modified by experience. This form of adaptive coping involves synaptic plasticity and neurogenesis, and low levels of proinflammatory cytokines, particularly IL-1β, are important neuromodulators as first suggested by Vitkovic et al. (2000) and reviewed by Yirmiya and Goshen, (2011).

IL-1/TLR signaling

Pharmacologic or genetic interference with cytokines before a convulsant challenge provides indirect but compelling evidence of their rapid release from constitutive pools of brain resident cells. For example, blockade of IL-1β biosynthesis with specific ICE/Caspase-1 inhibitors (Maroso et al., 2011; Ravizza et al., 2006), or inactivation of the biological actions of HMGB1 using receptor antagonists (Maroso et al., 2010), results in a significant delay in the onset time of kainate or

Biomarkers of brain inflammation and BBB damage

Based on the findings mentioned above, one can envisage that brain inflammation, the functions of astrocytes and microglia, endothelial cells and microvessels permeability may be considered a biomarker of tissue epileptogenicity. These pathophysiological features of brain response to injury could also be exploited for therapeutic purposes, for example to identify the patient population at risk to develop epilepsy as these patients might benefit from target-specific treatment (e.g.,

Conclusions

It has become clear over the past two decades that the brain is immunologically active. The brain innate immune response to injury or excessive neuronal activity is orchestrated mainly by its resident microglial and astrocytic populations, but even neurons play a key role. For example, prostaglandins produced by neuronal COX-2 regulate signaling pathways involved in synaptic plasticity under normal conditions, but in response to prolonged seizures the rapid induction of neuronal COX-2 triggers

Acknowledgments

Supported in part by NINDS grants 1 R21 NS074169, 1 U01 NS074509, and by the CounterAct program, Office of the Director, NIH, and NINDS grant number 2 U01 NS058158 (RD), and by Fondazione Cariplo, Fondazione Monzino and Regione Lombardia under Institutional Agreement n. 14501A (to AV).

References (146)

  • C.T. Ekdahl et al.

    Brain inflammation and adult neurogenesis: the dual role of microglia

    Neuroscience

    (2009)
  • K.C. Flanders et al.

    Transforming growth factor-betas in neurodegenerative disease

    Prog. Neurobiol.

    (1998)
  • A. Friedman et al.

    Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy

    Epilepsy Res.

    (2009)
  • M.A. Galic et al.

    Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

    Neurobiol. Dis.

    (2009)
  • I. Goshen et al.

    A dual role for interleukin-1 in hippocampal-dependent memory processes

    Psychoneuroendocrinology

    (2007)
  • L. Holtman et al.

    Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy

    Epilepsy Res.

    (2010)
  • K.H. Jung et al.

    Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus

    Neurobiol. Dis

    (2006)
  • A. Kumar et al.

    Epilepsy surgery in a case of encephalitis: use of 11C-PK11195 positron emission tomography

    Pediatr. Neurol.

    (2008)
  • A.Y. Lai et al.

    Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons

    J. Neuroimmunol.

    (2006)
  • J.J. Legos et al.

    Quantitative changes in interleukin proteins following focal stroke in the rat

    Neurosci. Lett.

    (2000)
  • V.L. Marcheselli et al.

    Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus. Inhibition by a platelet-activating factor antagonist

    J. Biol. Chem.

    (1996)
  • M. Maroso et al.

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

    Neurotherapeutics

    (2011)
  • M. Minami et al.

    Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain

    Biochem. Biophys. Res. Commun.

    (1991)
  • H.J. Murray et al.

    A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro

    Neuropharmacology

    (2003)
  • L.A. O'Neill et al.

    NF-kappa B: a crucial transcription factor for glial and neuronal cell function

    Trends Neurosci.

    (1997)
  • A. Pitkanen et al.

    Molecular and cellular basis of epileptogenesis in symptomatic epilepsy

    Epilepsy Behav.

    (2009)
  • C.R. Plata-Salaman et al.

    Interleukin-1 beta inhibits Ca2+ channel currents in hippocampal neurons through protein kinase C

    Eur. J. Pharmacol.

    (1994)
  • C.R. Plata-Salaman et al.

    Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions

    Brain. Res. Mol. Brain. Res.

    (2000)
  • N. Polascheck et al.

    The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy

    Exp. Neurol.

    (2010)
  • T. Ravizza et al.

    Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system

    Neuroscience

    (2006)
  • T. Ravizza et al.

    Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy

    Neurobiol. Dis.

    (2008)
  • T. Ravizza et al.

    Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production

    Neurobiol. Dis.

    (2008)
  • T. Ravizza et al.

    Inflammation and prevention of epileptogenesis

    Neurosci Lett.

    (2011)
  • N.J. Abbott et al.

    Astrocyte-endothelial interactions at the blood-brain barrier

    Nat. Rev. Neurosci.

    (2006)
  • K. Akassoglou et al.

    Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice

    J. Immunol.

    (1997)
  • S.M. Allan et al.

    Interleukin-1 and neuronal injury

    Nat. Rev. Immunol.

    (2005)
  • K. Andreasson

    Prostaglandin signalling in cerebral ischaemia

    Br. J. Pharmacol.

    (2010)
  • J.F. Annegers et al.

    The risk of unprovoked seizures after encephalitis and meningitis

    Neurology

    (1988)
  • E. Aronica et al.

    Inflammation in epilepsy: clinical observations

    Epilepsia

    (2011)
  • E. Aronica et al.

    Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy

    Eur. J. Neurosci.

    (2000)
  • S. Auvin et al.

    Inflammation exacerbates seizure-induced injury in the immature brain

    Epilepsia

    (2007)
  • S. Auvin et al.

    Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA

    Epilepsia

    (2010)
  • R.B. Banati

    Visualising microglial activation in vivo

    Glia

    (2002)
  • D. Battista et al.

    Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus

    Eur. J. Neurosci.

    (2006)
  • L. Bernardino et al.

    Inflammation and neurogenesis in temporal lobe epilepsy

    Curr. Drug Targets CNS Neurol. Disord.

    (2005)
  • P. Bezzi et al.

    CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity

    Nat. Neurosci.

    (2001)
  • M.E. Bianchi et al.

    High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity

    Immunol. Rev.

    (2007)
  • G.C. Blobe et al.

    Role of transforming growth factor beta in human disease

    N. Engl. J. Med.

    (2000)
  • T. Butler et al.

    Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia

    J. Neuroimaging

    (2011)
  • L.P. Cacheaux et al.

    Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis

    J. Neurosci.

    (2009)
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