ReviewInflammation and prevention of epileptogenesis
Highlights
► Pro-inflammatory molecules are upregulated during epileptogenesis. ► Brain inflammation favors neuronal network hyperexcitability. ► Targeting specific pro-inflammatory pathways result in antiepileptogenic affects.
Introduction
Various brain injuries in human such as neurotrauma, stroke, infection, febrile convulsions and status epilepticus are associated with the acute occurrence of seizures and an increased risk of developing epilepsy [11], [72], [91]. Experimental studies in rodents showed that these events induce a chronic decreased seizure threshold or the development of spontaneous seizures, supporting that CNS injury can lead to lasting hyperexcitability. These injuries trigger inflammatory processes in the brain, which are rapidly ensuing and long-lasting, raising the possibility that inflammatory mediators may contribute to the development of epileptogenesis, and the consequent precipitation of spontaneous seizures [19], [97], [100].
In particular, various studies have demonstrated that pro-epileptogenic events are followed by the rapid activation of glial cells and the concomitant production of various inflammatory molecules; both these phenomena remain up-regulated during epileptogenesis [51], [97], [100]. Experimental models of status epilepticus have been mostly used to study the temporal evolution of inflammatory processes, which first occur in activated microglia and astrocytes, and subsequently involve neurons and endothelial cells of the blood–brain barrier (BBB) [25], [29], [64], [76], [94], [105], [109]. The transient brain recruitment of blood-born granulocytes during epileptogenesis was also reported [76], suggesting these cells may also contribute to brain inflammation [33].
Evidence for increased synthesis of inflammatory mediators in the brain during epileptogenesis was corroborated by microarray analysis of transcripts of various classes of genes, showing prominently up-regulated inflammatory genes [39], [60], [62].
Pharmacological studies in experimental models of acute or chronic seizures, and assessment of seizure susceptibilty in genetically modified mice with impaired or overactive inflammatory signalling, demonstrated that pro-inflammatory mediators released from activated glia and neurons (e.g. citokines, “danger signals” such as High Mobility Group Box (HMGB) 1, prostaglandins, complement factors) contribute to the mechanisms of ictogenesis ([65]; for review see [51], [97], [99]). Moreover, the use of mice constitutively overexpressing IL-6 or TNF-α in astrocytes indicates that chronic inflammation can result in neuropathologic changes including seizures [16], [74].
Thus, the above evidence prompted further investigations into the possible involvement of inflammatory mediators in epileptogenesis. In this respect, two main experimental approaches have been adopted:
- 1.
To induce an inflammatory state in the brain by administering pro-inflammatory molecules, or by using mice that overexpress specific cytokines, and analyse both the short- and long-term consequences on neuronal excitability and seizure threshold.
- 2.
To interfere pharmacologically with specific inflammatory pathways activated during epileptogenesis, and evaluate the outcome based on onset, phenotype, frequency and duration of spontaneous seizures.
Section snippets
Adult rodents
The initial studies probed the effect of pre-existing brain inflammation on seizure susceptibility using adult mice systemically injected with lipopolysaccaride (LPS), a component of the outer wall of Gram-negative bacteria. Mice displayed a lower seizure threshold to pentylentetrazole (PTZ) and increased seizure severity between 1 and 12 h after LPS [80]. The LPS effect involved the activation of COX-2 and the subsequent production of prostaglandins, since SC-58236, a selective COX-2 inhibitor,
Effects of anti-inflammatory treatments on epileptogenesis
A series of pharmacological experiments performed during the epileptogenesis phase triggered by status epilepticus support the hypothesis that a pro-inflammatory challenge may contribute to long-term hyperexcitability leading to the onset of spontaneous seizures.
Treatment with minozac after status epilepticus in PN15 rats reversed the enhanced seizure susceptibility to kainic acid in adulthood; this drug decreased microglia activation and pro-inflammatory cytokines in hippocampus [84].
Various
Effects of pro-inflammatory cytokines on ion channels and receptors
The classic view explaining the effects of cytokines on neuronal excitability and viability relies on the ability of cytokines to induce the production of toxic mediators via autocrine or paracrine mechanisms [3]. Novel evidence shows that cytokines can rapidly alter the function of classical neurotransmitters by modulating their receptor assembly and phosphorylation at neuronal membranes [104]. For example, IL-1β produced by glial cells enhances NMDA-mediated inward Ca2+ currents in rat
Conclusions
Clinical and experimental evidence highlights brain inflammation as one key factor contributing to the epileptic process [99]. Thus, brain inflammation promotes increased neuronal excitability, decreases seizure threshold and is likely to be involved in the molecular, structural and synaptic changes characterizing epileptogenesis. Pharmacological experiments in animal models suggest that antiepileptogenic effects might be achieved by interfering with specific pro-inflammatory pathways
Acknowledgements
The authors are grateful to EPICURE (LSH-CT-2006-037315), Parent Against Childhood Epilepsy (P.A.C.E.) Foundation, Monzino and CARIPLO Foundations for their support to part of these studies.
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