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Over the past 10 years an increasing body of clinical and experimental evidence has provided strong support to the hypothesis that inflammatory processes within the brain might constitute a common and crucial mechanism in the pathophysiology of seizures and epilepsy (Vezzani et al., 2011). The first insights into the potential role of inflammation in human epilepsy were derived from clinical evidence indicating that steroids and other anti-inflammatory treatments displayed anticonvulsant activity in some drug-resistant epilepsies (Wirrell et al., 2005; Wheless et al., 2007). Additional evidence came from febrile seizures in people, which always coincide with, and are often caused by, a rise in the levels of pro-inflammatory agents (Dube et al., 2007). Evidence of immune system activation in some patients with seizure disorders, the high incidence of seizures in autoimmune diseases, and the discovery of limbic encephalitis as a cause of epilepsy led to the suggestion that immune and inflammatory mechanisms have roles in some forms of epilepsy (Aarli, 2000; Bien et al., 2007; Vincent and Bien, 2008; Vezzani et al., 2011).

Evidence is emerging that inflammation might be a consequence as well as a cause of epilepsy. Several inflammatory mediators have been detected in surgically resected brain tissue from human patients with refractory epilepsies, including temporal lobe epilepsy (TLE) and cortical dysplasia-related epilepsy (Choi et al., 2009; Vezzani et al., 2011). The finding that brain inflammation occurred in epilepsies that were not classically linked to immunological dysfunction highlighted the possibility that chronic inflammation might be intrinsic to some epilepsies, irrespective of the initial insult or cause, rather than being only a consequence of a specific underlying inflammatory or autoimmune aetiology. The mounting evidence for a role for inflammatory processes in human epilepsy has led to the use of experimental rodent models to identify putative triggers of brain inflammation in epilepsy, and to provide mechanistic insights into the reciprocal causal links between inflammation and seizures (Vezzani et al., 2011). Experimental studies have shown that seizure activity per se can induce brain inflammation, and that recurrent seizures perpetuate chronic inflammation. Seizure-associated cell loss can contribute to inflammation but is not a prerequisite for inflammation to occur. In addition, models of systemic or CNS infections suggested that pre-existing brain inflammation increases the predisposition to seizures, associated with alterations in neuronal excitability and enhanced seizure-induced neuropathology. Additional mechanistic insights into the role of inflammation in seizures and the development of epilepsy have been gained through use of pharmacological approaches that interfere with specific inflammatory mediators and from changes in seizure susceptibility in genetically modified mice with perturbed inflammatory pathways (Campbell et al., 1993; Kelley et al., 1999; Vezzani et al., 2000a; Balosso et al., 2005).

Inflammation consists of the production of a cascade of inflammatory mediators (a dynamic process), as well as anti-inflammatory molecules and other molecules induced to resolve inflammation, as a response to noxious stimuli (such as infection or injury), or immune stimulation, and is designed to defend the host against pathogenic threats. Inflammation is characterized by the production of an array of inflammatory mediators from tissue-resident or blood-circulating immuno-competent cells, and involves activation of innate and adaptive immunity. Both innate and adaptive immunity have been implicated in epilepsy, and microglia, astrocytes and neurons are believed to contribute to the innate immunity-type processes that cause inflammation of the brain. The brain has traditionally been considered an immunoprivileged site because of the presence of the blood–brain barrier (BBB), the lack of a conventional lymphatic system, and the limited trafficking of peripheral immune cells. Nevertheless, both the innate and adaptive immune responses are readily evoked within the CNS in response to pathogens, self-antigens, or tissue injury of several aetiologies. Microglia, astrocytes, neurons, BBB endothelial cells, and peripheral immune cells extravasating into brain parenchyma can all produce proinflammatory and anti- inflammatory molecules (Ransohoff et al., 2003; Banks and Erickson, 2010).

The contribution of each cell population to brain inflammation depends on the origin (for example, CNS versus systemic) and the type (for example, infectious versus sterile) of the initial precipitating event (Glass et al., 2010). The BBB represents a key regulatory element of the communication between intrinsic brain cells and peripheral immunocompe-tent cells. As noted above, an inflammatory response in the CNS can be induced in the absence of infection. Brain inflammation has been reported following ischaemic stroke or traumatic brain injury (TBI), and during chronic neurodegenerative diseases. In all these conditions, pronounced activation of microglia and astrocytes takes place in brain regions affected by the specific disease, and these cells act as major sources of inflammatory mediators. Recruitment of peripheral immune cells might also occur (Nguyen et al., 2002; Glass et al., 2010). The activation of innate immunity and the transition to adaptive immunity are mediated by a large variety of inflammatory mediators, among which cytokines, polypeptides that act as soluble mediators of inflammation, have a pivotal role (Akira et al., 2001; Nguyen et al., 2002).

These molecules include interleukins (ILs), interferons (IFNs), tumour necrosis factors (TNFs) and growth factors (for example, transforming growth factor (TGF)-β). Cytokines are released by immunocompetent and endothelial cells, as well as by glia and neurons in the CNS, thereby enabling communication between effector and target cells during an immune challenge or tissue injury. Following their release, cytokines interact with one or more cognate receptors. The most extensively studied prototypical inflammatory cytokines in the CNS are IL-1β, TNF and IL-6 (Allan and Rothwell, 2001; Bartfai et al., 2007). Cytokine activity can be regulated at multiple levels, including gene transcription, cleavage of cytokine precursors (for example, pro-IL-1β, pro-TNF) by specific proteolytic enzymes, and cellular release, as well as through receptor signalling (discussed below). All cell types in the brain seem capable of expressing cytokines and their receptors, with low basal expression of these molecules being rapidly up-regulated following CNS insults. Chemokines comprise a specific class of cytokines that act as chemoattractants to guide the migration of leukocytes from blood through the endothelial barrier into sites of infection or injury (Wilson et al., 2010). These cytokines also regulate microglial motility and neural stem cell migration, provide axon guidance during brain development, and promote angiogenesis, neurogenesis and synaptogenesis (Szekanecz and Koch, 2001; Semple et al., 2010). The release of chemokines is often stimulated by proinflammatory cytokines such as IL-1β.

Several mechanisms have been identified that attenuate the inflammatory response, indicating the importance of such strict control for homeostasis and prevention of injury. Regulatory mechanisms include production of proteins that compete with cytokines to bind their receptors, such as IL-1 receptor antagonist protein (IL-1ra), and decoy receptors that bind cytokines and chemokines but are incapable of signalling, thereby acting as molecular traps to prevent such ligands from interacting with biologically active receptors (Mantovani et al., 2001; Dinarello, 2009). Proteins that inhibit cytokine-induced signal transduction (for example, suppressor of cytokine signalling proteins) or transcription (for example, Nurr1-CoREST or activity transcription factor 3), as well as an array of soluble mediators with anti-inflammatory activities (such as IL-10 and TGF-β), are produced concomitantly with proinflammatory molecules to resolve inflammation (Blobe et al., 2000; Khuu et al., 2007; Baker et al., 2009). For example, glucocorticoids, via activation of glucocorticoid receptors and, consequently, down-regulation of nuclear factor-κB (NFκB) and activator protein 1 activity, inhibit innate immune responses and, hence, act as an endogenous anti-inflammatory feedback system. Proinflammatory cytokines are powerful enhancers of glucocorticoid levels in adrenal glands via corticotropin-releasing hormone and adrenocorticotropic hormone (ACTH). Glucocorticoids also elicit immunosuppressive effects through inhibition of leukocyte extravasation from the vasculature, and through regulation of T helper cell differentiation (Sapolsky et al., 1987; Elenkov et al., 1999). The CNS can also negatively regulate the inflammatory response in a reflexive manner, using the efferent activity of the vagus nerve to inhibit release of proinflammatory molecules from tissue macrophages (Vezzani et al., 2000a, 2011; Tracey, 2002).