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


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; 118. DOI:10.1016/j.brainresbull.2015.09.003 · 2.72 Impact Factor
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    • "Increasing evidence suggests a contribution of inflammation to the pathophysiology of seizures (Vezzani et al., 2011). Responses to acute seizures triggered by kainate induce rapid release of IL1B and TNF from microglia and astrocytes, and enhanced cytokine levels in serum and CSF have been found in epilepsy patients (Vezzani et al., 2008). We observe that application of IL1B, TNF and lipopolysaccharide in situ and in vivo exert robust uncoupling effects on the glial network, which is in line with findings in cell culture (John et al., 1999; Meme et al., 2006). "
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    ABSTRACT: Glial cells are now recognized as active communication partners in the central nervous system, and this new perspective has rekindled the question of their role in pathology. In the present study we analysed functional properties of astrocytes in hippocampal specimens from patients with mesial temporal lobe epilepsy without (n = 44) and with sclerosis (n = 75) combining patch clamp recording, K(+) concentration analysis, electroencephalography/video-monitoring, and fate mapping analysis. We found that the hippocampus of patients with mesial temporal lobe epilepsy with sclerosis is completely devoid of bona fide astrocytes and gap junction coupling, whereas coupled astrocytes were abundantly present in non-sclerotic specimens. To decide whether these glial changes represent cause or effect of mesial temporal lobe epilepsy with sclerosis, we developed a mouse model that reproduced key features of human mesial temporal lobe epilepsy with sclerosis. In this model, uncoupling impaired K(+) buffering and temporally preceded apoptotic neuronal death and the generation of spontaneous seizures. Uncoupling was induced through intraperitoneal injection of lipopolysaccharide, prevented in Toll-like receptor4 knockout mice and reproduced in situ through acute cytokine or lipopolysaccharide incubation. Fate mapping confirmed that in the course of mesial temporal lobe epilepsy with sclerosis, astrocytes acquire an atypical functional phenotype and lose coupling. These data suggest that astrocyte dysfunction might be a prime cause of mesial temporal lobe epilepsy with sclerosis and identify novel targets for anti-epileptogenic therapeutic intervention. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 03/2015; 138(5). DOI:10.1093/brain/awv067 · 9.20 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; 167(1). DOI:10.1016/j.schres.2014.10.019 · 3.92 Impact Factor
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