The role of cytokines in the pathophysiology of epilepsy
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.
- SourceAvailable from: Sabina Berretta
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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). "
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 · 4.43 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   . "
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 · 2.37 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). "
ABSTRACT: We showed previously that the number and time of spike-wave discharges (SWDs) were increased after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), an effect, which was completely abolished by cyclooxygenase-2 (COX-2) inhibitor indomethacin (IND) pretreatment in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. These and other results suggest that injection of LPS to genetically absence epileptic animals, such as WAG/Rij rats, may allow us to investigate relationships between absence epilepsy and LPS evoked neuroinflammation processes. However, LPS may evoke different effects on absence epileptic activity in various animal strains. Thus, to extend our previous results, we injected two doses of LPS (50μg/kg and 350μg/kg i.p.) alone and in combination with IND (10mg/kg IND i.p.+50μg/kg LPS) into rats of two model animal strains (WAG/Rij rats; GAERS rats: Genetic Absence Epileptic Rats from Strasbourg) and into Long Evans rats. The effects of treatments on SWD number and SWD duration were examined. Both doses of LPS increased the SWD number and the total time of SWDs dose-dependently during the whole 4-hour recording period, which was abolished by IND pretreatment in all three investigated strains. These results extend our previous results suggesting that our methods using LPS injection into freely moving absence epileptic rats is applicable not only in well-established animal models of absence epilepsy such as WAG/Rij rats and GAERS rats but also in Long Evans rats to investigate links between inflammation and absence epilepsy.Brain research bulletin 04/2014; DOI:10.1016/j.brainresbull.2014.03.003 · 2.97 Impact Factor