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Experimental evidence has shown that the induction of status epilepticus (SE) in rodents using either electrical stimulation of limbic brain regions or systemic, as well as intracerebral, administration of convulsant drugs, elicits pronounced brain inflammation involving glia, endothelial cells and, neurons (for review see Vezzani & Granata, 2005; Oby & Janigro, 2006; Vezzani & Baram, 2007). In adult rat or mouse, the induction in brain of interleukin-1beta (IL-1β), a prototypical inflammatory cytokine, occurs within the first 60 min of SE and is observed in the areas of seizure origin and generalization (Dhote et al., 2007; Ravizza et al., 2008a). Upregulation of this cytokine in glia precedes seizure-associated neuronal cell loss and may contribute to it (Bernardino et al., 2005; Ravizza et al., 2008a).

Brain inflammation induced by SE can become chronic and is detectable at significant levels also during the epileptogenesis phase preceding the onset of spontaneous seizures, as well as in chronic epileptic tissue (De Simoni et al., 2000; Gorter et al., 2006; Ravizza et al., 2008a). The induction of inflammatory processes by SE is age-dependent, occurring in rodent from postnatal day 15 onward (Rizzi et al., 2003), with the notable exception of hyperthermia-induced prolonged seizures (Vezzani & Baram, 2007). In this febrile seizure model, brain inflammation is indeed detectable in 9-day-old rats and persists for at least 24 h after the end of SE. No irreversible neuronal cell loss occurs in this model, indicating that inflammation is not a mere consequence of cell death. However, studies in adult rodent brain suggest that the presence of degenerating neurons may contribute to perpetuate brain inflammation (Vezzani et al., 1999; Ravizza et al., 2008a).

Pharmacologic, biochemical, and electrophysiologic studies have shown that brain inflammation contributes to promote neuronal network excitability, acting at several steps, namely, by altering glutamate receptor subunit composition and membrane receptor levels, N-methyl-d-aspartate (NMDA)–dependent calcium fluxes into neurons, extracellular glutamate levels, and blood–brain barrier permeability function (Vezzani & Granata, 2005; Oby & Janigro, 2006; Marchi et al., 2007; Fabene et al., 2008).

In particular, pharmacologic studies in in vivo models of seizures show that inhibition of specific proinflammatory pathways such as blockade of the production of IL-1β or prostaglandin E2 or prevention of blood–brain barrier leakage dramatically reduces seizures and may retard epileptogenesis (Fabene et al., 2008; Vezzani & Granata, 2005; Jung et al., 2006; Marchi et al., 2007; Ravizza et al., 2008b).

Mimicking systemic infection by administration of lipopolysaccharide (LPS) in adult and immature rats reduces the threshold for seizure induction; in immature rodents LPS administration transiently increases brain cytokines and primes immature rats to develop more damage during SE (Auvin et al., 2007). In addition, seizure threshold is reduced and seizure-induced damage is enhanced after SE elicited in adult rats preexposed to LPS at postnatal day 7 or 14 (Galic et al., 2008). Therefore, a transient inflammatory event occurring postnatally induces a chronic hyperexcitable neuronal network in the hippocampus.

Finally, evidence of the presence of brain inflammation has been reported also in human epileptic tissue, and increased cytokine levels have been measured in blood following different kinds of seizures in humans (Vezzani & Granata, 2005; Ravizza et al., 2008a).

These findings highlight that brain inflammation plays a role in the mechanisms of hyperexcitability occurring during repetitive or prolonged seizures; the establishment of chronic inflammation after SE or the occurrence of infection-mimicking events can prime persistent excitability changes and may contribute to epileptogenesis.

Acknowledgment

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Disclosure: None of the authors have any conflict of interest to declare.

References

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