The role of cytokines in the pathophysiology of epilepsy

Mario Negri Institute for Pharmacological Research, Department of Neuroscience, Via G La Masa, 19 Milano, Italy.
Brain Behavior and Immunity (Impact Factor: 6.13). 09/2008; 22(6):797-803. DOI: 10.1016/j.bbi.2008.03.009
Source: PubMed

ABSTRACT Recent findings in experimental models and in the clinical setting highlight the possibility that inflammatory processes in the brain contribute to the etiopathogenesis of seizures and to the establishment of a chronic epileptic focus. Prototypical inflammatory cytokines such as IL-1 beta, TNF-alpha and IL-6 have been shown to be overexpressed in experimental models of seizures in brain areas of seizure generation and propagation, prominently by glia and to a lesser extent by neurons. Cytokines receptors are also upregulated, and the related intracellular signalling is activated, in both cell populations highlighting autocrine and paracrine actions of cytokines in the brain. Cytokines have been shown to profoundly affect seizures in rodents; in particular, IL-1 beta is endowed of proconvulsant activity in a large variety of seizure models. The recent demonstration of functional interactions between cytokines and classical neurotransmitters such as glutamate and GABA, suggest the possibility that these interactions underlie the cytokine-mediated changes in neuronal excitability, thus promoting seizure phenomena and the associated neuropathology. These findings point out at novel glio-neuronal communications in diseased conditions and highlight potential new targets for therapeutic intervention.

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    • "For instance, interleukins 1 and 6, tumor necrosis factor α, transforming growth factor β1 and brain derived growth factor have been consistently found to be altered in psychiatric illnesses such as mood disorders and schizophrenia and suggested to mediate interactions between these illnesses, inflammation and stress (Kim et al., 2004; Chavarria-Siles et al., 2007; Hashimoto, 2010; Catena-Dell'Osso et al., 2013; Fineberg and Ellman, 2013; Poon et al., 2013; Barbosa et al., 2014; Rosenblat et al., 2014). Several of these cytokines were shown to directly affect GABAergic transmission, impacting GABA A-mediated synaptic strength and dendritic homeostasis (Wang et al., 2000; Beattie et al., 2002; Stellwagen et al., 2005; Vezzani et al., 2008; Benes, 2010; Sun et al., 2010), pointing to the need to better understand, as well as control for, the relationships between immune factors and neurotransmission in psychiatric disorders (Benes, 2010). "
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    • "Moreover, it is now an accepted clinical idea that imbalances in the immune system, perhaps caused by interactions of multiple cytokines, cause or contribute to many neurodevelopmental disorders [18,19]. Elevated levels of pro-inflammatory cytokines have been associated with autism and schizophrenia, Down syndrome and epilepsy [20] [21] [22]. "
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    Immunology Letters 08/2014; 162(1). DOI:10.1016/j.imlet.2014.08.003 · 2.37 Impact Factor
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    • "IL-1␤ and TNF-␣ may diminish the chloride current and may enlarge excitatory glutamatergic neurotransmission (Mlodzikowska-Albrecht et al., 2007; Vezzani and Granata, 2005) causing decreased seizure threshold and enhanced neuronal hyperexcitability (Riazi et al., 2010; Rodgers et al., 2009; Vezzani et al., 2011, 2013). In addition, GABA (A) -mediated inhibition decreasing influence and AMPA-dependent excitation increasing effect of TNF␣ were also demonstrated (Mlodzikowska-Albrecht et al., 2007; Vezzani et al., 2008). Imbalanced intracortical inhibitory and excitatory mechanisms result in cortical hyperexcitability during SWDs (Chen et al., 2011; Coenen and Van Luijtelaar, 2003; Depaulis and Van Luijtelaar, 2005; Van Luijtelaar et al., 2011). "
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