Invited ReviewThe role of cytokines in the pathophysiology of epilepsy
Introduction
Epilepsy comprises a group of neurological disorders characterized by the periodic occurrence of spontaneous seizures and affecting about 1% of the population worldwide. About 30% of epileptic patients are defined pharmacoresistant since they do not adequately respond to therapies and in these patients the surgical removal of the epileptic focus is often the only therapeutic option to achieve seizure control (Kwan and Brodie, 2006). Pathologic brain specimens from patients with drug resistant epilepsy demonstrated the occurrence of marked reactive gliosis in epileptogenic tissue. Recent studies have implicated glial cells in novel physiological roles in the CNS including modulation of synaptic transmission; therefore, it is plausible that glial cells may have a functional role in the hyperexcitability phenomena which underlie seizures in epilepsy. Alterations in distinct astrocyte membrane channels, receptors and transporters (Seifert et al., 2006) and phenotypic changes in activated microglial cells have been described in chronic epileptic tissue (Boer et al., 2006, Ravizza et al., 2008) and they are possibly associated with the epileptic state characterized by recurrent spontaneous seizures.
Several inflammatory mediators are expressed in activated glial cells in epileptogenic tissue raising the key question of whether this inflammatory process is a mere epiphenomenon of seizure activity and the associated neuronal injury, or if it may contribute to the pathology and if so, then how. Inflammation has been implicated in the progressive nature of neurodegenerative diseases (Griffin, 2006) and inflammatory processes are now considered key contributors to acute and chronic neurodegenerative disorders, such as ischemic stroke and Alzheimer’s disease (Allan et al., 2005). Most recently, experimental and clinical findings support a crucial role of inflammatory processes in epilepsy (Vezzani and Granata, 2005) in particular, in the mechanisms underlying the generation of seizures (ictogenesis) and the transformation of a normal neuronal network into a seizure-generating one (i.e. epileptogenesis, Pitkanen and Sutula, 2002). Insight into the role of the cytokines, especially of interleukin-1β (IL-1β), in the evolution of epilepsy has been gained by molecular and pharmacological studies in in vivo models and the use of genetically engineered mice with perturbed cytokine signalling. These approaches are leading to a radically modified view of the role of cytokines in epilepsy which may be germane to other neurological diseases.
Section snippets
Glia as a source of cytokines in epileptic tissue
Experimental evidence in rodent models has demonstrated that seizures induce high levels of inflammatory mediators in brain regions involved in the generation and propagation of epileptic activity. In particular, a rapid-onset inflammatory response in glia is triggered by seizures induced by chemoconvulsants or by electrical stimulation (De Simoni et al., 2000, Eriksson et al., 1999, Gorter et al., 2006, Plata-Salaman et al., 2000, Ravizza and Vezzani, 2006, Shinoda et al., 2003, Turrin and
Cytokine receptors in seizures
Investigation of the pattern of expression of cytokine receptors in seizures is important to give clues of the cell populations targeted by the cytokines. IL-1R1, which mediates the biological responses to IL-1β, is barely detectable in normal brain tissue but it is rapidly increased (<2 h) in hippocampal neurons after seizures, and a later wave of expression is observed during epileptogenesis also in astrocytes (Ravizza and Vezzani, 2006, Ravizza et al., 2008), thus indicating both paracrine
Chronic inflammation and seizure susceptibility
Experimental evidence in rodents shows that a large variety of brain insults (i.e. neurotrauma, stroke, infection, perinatal injury, febrile seizures, etc.) can induce inflammation in the brain (Vezzani and Granata, 2005). These injuries in humans represent risk factors for the development of epilepsy, suggesting that an inciting event, even if subclinical, occurring at birth or during the lifetime may initiate a cascade of chronic inflammatory processes in the CNS that contributes to set the
Clinical studies
The first clinical insight into a possible role of inflammation in epilepsy is the evidence that selected antiinflammatory drugs, including steroids, display anticonvulsant activity and may control seizures which are otherwise refractory to classical antiepileptic drugs (Vezzani and Granata, 2005).
Subsequently, several reports showed increased cytokines in serum and CSF in patients with epilepsy. For example, recent tonic–clonic seizures induce higher IL-6 levels and lower IL-1Ra-to-IL-1α ratio
Functional and pharmacological studies in experimental models
The role of cytokines in seizures and epileptogenesis has been investigated using genetically-modified mice with a perturbed cytokine system or by pharmacological means using receptor antagonists or cytokine synthesis inhibitors, or by intracerebral injection of the cytokines themselves. In this respect, most of the data so far available concern IL-lβ and TNF-α. The preapplication of IL-1β in rodent brain, by using concentrations within the range of those endogenously produced by seizures,
IL-1β
Recent evidence demonstrated that IL-1R1 colocalizes on hippocampal pyramidal neurons with the N-methyl-d-aspartate (NMDA) receptor, a subtype of glutamate receptors crucially involved in the onset and spread of seizures. IL-1β via activation of neuronal IL-1R1 induces Src kinase-mediated tyrosine phosphorylation of the NR2B subunit of the NMDA receptor. As a consequence of this action, NMDA receptor-mediated Ca2+ influx into neurons is enhanced by IL-1β and this effect plays a role in
The role of cytokines in seizure-associated neuronal damage
In the mature rodent brain, status epilepticus leads to a loss of neurons in the hippocampal formation and in other forebrain areas involved in the epileptic activity (Majores et al., 2007). Cytokines and other inflammatory mediators have been shown to contribute to both excitotoxic and apoptotic neuronal death (Allan et al., 2005), highlighting the possibility that the production and release of cytokines during seizures by glia and/or by cells of the adaptive immune system may contribute to
Concluding remarks
The initiation of a pro-epileptogenic inflammatory response within the CNS can be envisaged as a consequence to an intrinsic “injurious” event, and the experimental studies in models of epileptogenesis following an episode of status epilepticus support this possibility. The initial challenge, however, may also originate within peripheral lymphoid tissues, for example when epilepsy evolves after systemic infectious diseases, encephalitis, or in prolonged seizures associated with fever.
A genetic
Acknowledgments
The authors are grateful to EPICURE (LSH-CT-2006-037315), Negri Weizmann Programme, Dana Foundation and Fondazione Monzino for their important contributions to part of these studies. We thank Prof. T. Bartfai for contributing to Fig. 2.
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