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: 5.89). 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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    • "matory cytokines such as IL-1 and TNF-by means of TLR4 (Mlodzikowska-Albrecht et al., 2007; Vezzani et al., 2011), (iii) IL-1 may increase excitatory glutamatergic neurotransmission and may diminish the GABAergic transmission (Mlodzikowska- Albrecht et al., 2007; Vezzani and Granata, 2005) and (iv) TNF-may decrease and increase GABA A receptor-induced inhibition and -amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-dependent excitation, respectively (Stellwagen et al., 2005; Vezzani et al., 2008, 2011). All of these effects above may evoke imbalance between excitatory/inhibitory processes in the brain and enhance excitation in the thalamo-cortical/corticothalamic circuitry in WAG/Rij rats which may aggravate SWDs in WAG/Rij rats (Coenen and Van Luijtelaar, 2003; Kovács et al., 2006, 2014a; Van Luijtelaar et al., 2011, 2012). "
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    ABSTRACT: We showed previously that the number of spike-wave discharges (SWDs) was increased after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), inosine (Ino) and muscimol alone whereas i.p. guanosine (Guo), uridine (Urd), bicuculline, theophylline and (+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine maleate (MK-801) alone decreased the SWD number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. These drugs may exert their effects on absence epileptic activity mainly via proinflammatory cytokines-evoked increase in cortical excitability (such as LPS), GABAergic system (LPS, Ino, Urd, muscimol and bicuculline), glutamatergic system (LPS, Guo and MK-801) and adenosinergic system (LPS, Ino, Guo, Urd and theophylline). Both GABAergic system and glutamatergic system are involved in the pathomechanism of absence epilepsy, the LPS-evoked increase in absence epileptic activity and the pro- or antiepileptic effects of non-adenosine (non-Ado) nucleosides Ino, Guo and Urd. Moreover, Ino, Guo and Urd have modulatory effects on inflammatory processes. Thus, we investigated whether Ino, Guo and Urd have also modulatory influence on LPS-evoked increase in SWD number using two different concentrations of each nucleoside in WAG/Rij rats. We demonstrated that Ino dose-dependently aggravated whereas Guo and Urd attenuated the LPS-evoked increase in SWD number. Our results suggest that different nucleosides have diverse effects on LPS-induced changes in absence epileptic activity.
    Brain research bulletin 09/2015; DOI:10.1016/j.brainresbull.2015.09.003 · 2.72 Impact Factor
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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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    ABSTRACT: In the past 25 years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of the human brain.
    Schizophrenia Research 11/2014; DOI:10.1016/j.schres.2014.10.019 · 3.92 Impact Factor
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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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    ABSTRACT: Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with several neurodevelopmental disorders and their role in neuronal development is being investigated. To assess the possible influence of cytokines on the onset of intellectual disability (ID), we studied the polymorphisms of thirteen proinflammatory cytokine genes in 81 patients and 61 healthy controls. We demonstrated a significant association of interleukin-6 (IL-6) single-nucleotide polymorphism (SNP) (-174 G/C and nt565 G/A), and interleukin-1 receptor antagonist (IL-1RA) (Mspa-I 11100) SNP with ID. Moreover, the IL-6 SNPs is an unfavorable genetic predisposition for females. The evaluation of circulating levels of IL-6 and IL-1RA showed that the serum concentrations of IL-6 were significantly higher in ID patients than in controls. These data suggest that functional cytokine gene polymorphisms may influence the development of ID.
    Immunology Letters 08/2014; 162(1). DOI:10.1016/j.imlet.2014.08.003 · 2.51 Impact Factor
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