Invited reviewThe role of inflammation in epileptogenesis
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)
- et al.
Complement activation in experimental and human temporal lobe epilepsy
Neurobiol. Dis.
(2007) - et al.
Inflammation enhances epileptogenesis in immature rat brain
Neurobiol. Dis.
(2010) - et al.
Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus
Brain Res.
(1999) - et al.
Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus
Neuroscience
(1991) - et al.
Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus
Behav. Brain Res.
(2002) - et al.
Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection
Brain Behav. Immun.
(2009) - et al.
Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus
Brain Res.
(1993) - et al.
Lipid signaling: sleep, synaptic plasticity, and neuroprotection
Prostaglandins Other Lipid Mediat.
(2005) - et al.
Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures
Neuropharmacology
(1994) - et al.
Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production
Brain Res.
(2005)