Recent EPITARGET Publications sorted by PubMed ID
E.A. van Vliet, W.M. Otte, W.J. Wadman, E. Aronica, G. Kooij, H.E. de Vries, R.M. Dijkhuizen, J.A. Gorter. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging. Epilepsia 2016, 57(1):59-69.
The mammalian Target Of Rapamycin (mTOR) pathway has received increasing attention as potential anti-epileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this effect via restoration of blood-brain barrier (BBB) dysfunction, contrast-enhanced Magnetic Resonance Imaging (CE-MRI) was used to determine BBB permeability throughout epileptogenesis. We observed an initial slow recovery of BBB function in rapamycin-treated epileptic rats, indicating that rapamycin does not reduce seizure activity by a gradual recovery of BBB integrity. During the chronic phase, reduced BBB leakage was evident, which could contribute to the decreased seizure frequency in post-status epilepticus rats treated with rapamycin. Furthermore, the data show that CE-MRI (using step-down infusion with gadobutrol) can be used as biomarker for monitoring the effect of drug therapy in rats.
E.A. van Vliet, W.M. Otte, W.J. Wadman, E. Aronica, G. Kooij, H.E. de Vries, R.M. Dijkhuizen, J.A. Gorter. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms. Epilepsia 2016, 57(1):70-8.
Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced Magnetic Resonance Imaging (MRI) study we showed that the mTOR inhibitor rapamycin reduced BBB leakage and seizure activity during the chronic epileptic phase. Considering rapamycin’s role on growth and immune response, the potential therapeutic effects of rapamycin after status epilepticus with emphasis on brain inflammation and brain vasculature were investigated. (Immuno)histrochemistry showed that local blood vessel density, activated microglia and astrogliosis were reduced in rapamycin-treated rats compared to vehicle-treated rats. In vitro studies showed that rapamycin could attenuate TNFa induced endothelial barrier breakdown. These data suggest that rapamycin improves BBB function during the chronic epileptic phase by a reduction of local brain inflammation and blood vessel density that can contribute to a milder form of epilepsy.
Grote A, Robens BK, Blümcke I, Becker AJ, Schoch S, Gembé E. LRP12 silencing during brain development results in cortical dyslamination and seizure sensitization. Neurobiol. Dis. 2016 Feb;86:170-6
Cortical maturation is a key precondition for proper function. Focal cortical dysplasias (FCDs) are increasingly encountered as causes of therapy refractory epilepsies. However, the molecular basis is only incompletely understood. The present manuscript suggests
LRP12 and lipoprotein homeostasis as potential molecular target structures for the emergence of epilepsy-associated FCDs of the so-called type Ib. The neuropathological FCD subtypes have substantially different post surgical outcome with respect to seizures. LRP12 immunohistochemistry may be of particular value as diagnostic biomarker. The present manuscript is based on the interaction between two major FP7 consortia, i.e. EPITARGET and Prof. Ingmar Blümcke from DeSire.
Nikitidou Ledri L, Melin E, Christiansen SH, Gøtzsche CR, Cifra A, Woldbye DP, Kokaia M. Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors. Neurobiol. Dis. 2016 Feb;86:52-61
In this paper, a conceptually novel framework reflecting a plausible clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i)whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor-based gene therapy approach targeting only the seizure generating focus unilaterally can decrease seizure frequency in this chronic model of epilepsy.
Bröer, S, Löscher W. Novel combinations of phenotypic biomarkers predict development of epilepsy in the lithium–pilocarpine model of temporal lobe epilepsy in rats. Epilepsy Behav. 2015 Dec;53:98-107
The discovery and validation of biomarkers in neurological and neurodegenerative diseases is an important challenge for early diagnosis of disease and for the development of therapeutics. The goal of the present prospective study in the lithium-pilocarpine model of epilepsy in rats was to determine the discriminative utility of combinations of phenotypic biomarkers by examining their ability to predict epilepsy. To determine whether a biomarker or combination of biomarkers performed better than chance at predicting epilepsy after SE, derived data underwent receiver operating characteristic (ROC) curve analyses. Our data indicate that a combinatorial biomarker approach may overcome the challenge of individual variability in the prediction of epilepsy.
van Loo KM, Schaub C, Pitsch J, Kulbida R, Opitz T, Ekstein D, Dalal A, Urbach H, Beck H, Yaari Y, Schoch S, Becker AJ. Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat Commun. 2015 Oct 26;6:8688
Scientists at the University of Bonn and the Hebrew University of Jerusalem (Israel) have decoded a central signal cascade associated with epileptic seizures. If the researchers blocked a central switch in epileptic mice, the frequency and severity of the seizures decreased. Using a novel technology, it was possible to observe the processes prior to the occurrence of epileptic seizures in living animals. The results are now being published in the journal "Nature Communications".
Vezzani A, Fujinami RS, White HS, Preux PM, Blümcke I, Sander JW, Löscher W. Infections, inflammation and epilepsy. Acta Neuropathol. 2016 Feb;131(2):211-34
Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumors may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered.
Löscher W, Hirsch LJ, Schmidt D. The enigma of the latent period in the development of symptomatic acquired epilepsy - Traditional view versus new concepts. Epilepsy Behav. 2015 Nov;52(Pt A):78-92
A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.
Roncon P, Soukupovà M, Binaschi A, Falcicchia C, Zucchini S, Ferracin M, Langley SR, Petretto E, Johnson MR, Marucci G, Michelucci R, Rubboli G, Simonato M. MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy--comparison with human epileptic samples. Scientific reports. 2015 Sep 18; 5:14143
The identification of epilepsy biomarkers would help to identify patients that will develop epilepsy following brain injury and to inform new treatment strategies. MicroRNAs (miRNAs) are an attractive option in this direction. In this study, miRNA microarrays were performed on a brain cell population (hippocampal granule cells, GC) and on plasma, at different time points in the natural history of pilocarpine-induced epilepsy in rats. Sixty-three miRNAs were differentially expressed in GC at the different time points, and miRNAs altered in the chronic phase were found altered also in human GC obtained from epilepsy surgery. Analysis of plasma samples revealed different levels between control and pilocarpine-treated animals for 27 miRNAs. Those miRNAs that are altered in plasma before the first spontaneous seizure may be proposed as biomarkers of epileptogenesis.
Vezzani A, Dingledine R, Rossetti AO. Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application. Expert Rev Neurother. 2015;15(9):1081-92
Status epilepticus (SE) is a life-threatening neurological emergency often refractory to available treatment options. It is a very heterogeneous condition in terms of clinical presentation and causes, which besides genetic, vascular and other structural causes also include CNS or severe systemic infections, sudden withdrawal from benzodiazepines or anticonvulsants and rare autoimmune etiologies. Treatment of SE is essentially based on expert opinions and antiepileptic drug treatment per se seems to have no major impact on prognosis. There is, therefore, urgent need of novel therapies that rely upon a better understanding of the basic mechanisms underlying this clinical condition. Accumulating evidence in animal models highlights that inflammation ensuing in the brain during SE may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent of an infection or auto-immune cause; this evidence encourages reconsideration of the treatment flow in SE patients.
Shen HY, van Vliet EA, Bright KA, Hanthorn M, Lytle NK, Gorter J, Aronica E, Boison D. Glycine transporter 1 is a target for the treatment of epilepsy. Neuropharmacology. 2015 Dec;99:554-65
Using two different rodent models of temporal lobe epilepsy (TLE) we first demonstrated robust overexpression of glycine transporter 1 (GlyT1) in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.
Lal D, Steinbrücker S, Schubert J, Sander T, Becker F, Weber Y, Lerche H, Thiele H, Krause R, Lehesjoki AE, Nürnberg P, Palotie A, Neubauer BA, Muhle H, Stephani U, Helbig I, Becker AJ, Schoch S, Hansen J, Dorn T, Hohl C, Lüscher N, Epicure consortium, EuroEPINOMICS-CoGIE consortium, von Spiczak S, Lemke JR. Investigation of GRIN2A in common epilepsy phenotypes. Epilepsy Res. 2015 Sep;115:95-9
Genetic analyses were carried out with respect to mutations in the GRIN2A gene in different epilepsy syndromes. As major result, alterations were found in idiopathic pediatric focal epilepsies, whereas generalized epilepsies and adult onset focal epilepsies did not show significant alterations.
Roseti C, van Vliet EA, Cifelli P, Ruffolo G, Baayen JC, Di Castro MA, Bertollini C, Limatola C, Aronica E, Vezzani A, Palma E. GABAA currents are decreased by IL-1β in epileptogenic tissue of temporal lobe epilepsy patients: implications for ictogenesis. Neurobiol Dis. 2015 Oct;82:311-20
We report the novel finding that pathophysiological concentrations of IL-1β decreased the amplitude of GABA-evoked currents by up to 30% in specimens from patients with temporal lobe epilepsy (TLE) with or without hippocampal sclerosis, but not in control tissues. This effect was reproduced by patch-clamp recordings on neurons in entorhinal cortex slices from rats with chronic epilepsy, and was not observed in control slices. In TLE specimens from humans, the IL-1β effectwas mediated by IL-1R1 and PKC. We also showed that IL-1R1 and IRAK1, the proximal kinase mediating the IL-1R1 signaling, are both up-regulated in the TLE compared with control specimens, thus supporting the idea that the IL-1β/IL-R1 axis is activated in human epilepsy. Our findings suggest a novel mechanism possibly underlying the ictogenic action of IL-1β, thus suggesting that this cytokine contributes to seizure generation in human TLE by reducing GABA-mediated neurotransmission.
Levy N, Milikovsky DZ, Baranauskas G, Vinogradov E, David Y, Ketzef M, Abutbul S, Weissberg I, Kamintsky L, Fleidervish I, Friedman A, Monsonego A. Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice. Journal of immunology (Baltimore, Md. : 1950). 2015 Aug 15;195(4):1713-22
The pathway identified as sufficient to induce epilepsy following brain injury (albumin-activated TGF-β signaling) is known to be associated with an inflammatory response. Here we set out to explore the cell populations and the inflammatory mediators involved in this process. Our results highlight an inflammatory reaction executed specifically by astrocytes. We show that astrocytic TGF-β1 signalling promotes rapid release of the IL-6 cytokine, and that IL-6 is in turn associated with impaired astrocyte-neuron interactions and epilepsy. We suggest that therapeutic strategies supressing IL-6 expression/signaling may prove beneficial for the prevention of post injury epilepsy.
Löscher, W. Single versus combinatorial therapies in status epilepticus: Novel data from preclinical models. Epilepsy Behav. 2015 Aug;49:20-5
Drug-refractory status epilepticus (RSE) is a major medical emergency with a mortality of up to 40% and the risk of severe long-term consequences. Animal models are important in developing treatment strategies for more effective termination of SE and prevention of its long-term outcomes. In this review, different rational polytherapies for SE, which are more effective than monotherapies, are discussed, including a novel polytherapy recently developed by our group.
Michel K, Müller JA, Oprişoreanu AM, Schoch S. The presynaptic active zone: A dynamic scaffold that regulates synaptic efficacy. Exp Cell Res. 2015 Jul 15;335(2):157-64.
Plasticity of synaptic structures is an important target of temporal lobe epilepsy. The present manuscript reveals, that RIM1α is critically important in the adaptive plasticity of the presynapse to transiently increase the electrical activity of the brain. Based on these analyses new biomarkers for synaptic aberrant plasticity in epileptogenesis may emerge.
Lehto LJ, Garwood M, Gröhn O, Corum CA. Phase imaging in brain using SWIFT. J Magn Reson. 2015 Mar;252:20-8
“MRI phase contrast behavior in zero echo time SWIFT pulse sequence in brain was studied. We were able to show that SWIFT phase images behaves most part the same way as phase contrast obtained with gradient echo pulse sequence but also contains direct contribution from myelin water pool. Therefore SWIFT phase imaging may provide sensitive tool to assess white matter damage after brain injury during epileptogenesis.”
Johnson MR, Behmoaras J, Bottolo L, Krishnan ML, Pernhorst K, Santoscoy PL, Rossetti T, Speed D, Srivastava PK, Chadeau-Hyam M, Hajji N, Dabrowska A, Rotival M, Razzaghi B, Kovac S, Wanisch K, Grillo FW, Slaviero A, Langley SR, Shkura K, Roncon P, De T, Mattheisen M, Niehusmann P, O'Brien TJ, Petrovski S, von Lehe M, Hoffmann P, Eriksson J, Coffey AJ, Cichon S, Walker M, Simonato M, Danis B, Mazzuferi M, Foerch P, Schoch S, De Paola V, Kaminski RM, Cunliffe VT, Becker AJ, Petretto E. Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nat Commun. 2015 Jan 23;6:6031
A systems neurobiological approach was carried out in complementary human epileptic brain tissue of patients with focal pharmacoresistant epilepsies and animal models, i.e. status epilepticus models of mice as well as zebrafishes. Respective analyses revealed Sestrin3 as a major regulator of pro-epileptic molecular networks. These data will be important to derive new therapeutic and biomarker perspectives.
Esposito L, Drexler JF, Braganza O, Doberentz E, Grote A, Widman G, Drosten C, Eis-Hübinger AM, Schoch S, Elger CE, Becker AJ, Niehusmann P. Large-scale analysis of viral nucleic acid spectrum in temporal lobe epilepsy biopsies. Epilepsia. 2015 Feb;56(2):234-43
Inflammatory processes promote the onset of focal epilepsies in the temporal lobe. A large number of biopsy tissue specimens of patients with pharmacoresistant temporal lobe epilepsy were subjected to screen for neurotropic viruses as potential biomarkers of the development of temporal lobe epilepsy. Respective analyses revealed a high virus load of HHV-6B which may constitute a permissive factor of inflammatory processes of the hippocampal formation in the pathogenesis of temporal lobe epilepsy.
Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015 Sep;96(Pt A):70-82
This work shows that cytokines display a direct neuromodulatory role in both the central and peripheral nervous systems; this role is distinct from their immune and inflammatory properties. In particular, cytokines modulate voltage-gated and receptor-operated ion channels and presynaptic neurotransmitter release. Cytokines affect neuronal excitability also indirectly by activating glial cells. The review also reports evidence on the physiological role of cytokines in synaptic transmission and plasticity. Finally, there is discussion related to the pathological outcomes mediated by excessive cell exposure to cytokines, in particular neuropathological effects related to cell loss and hyperexcitability.
Rossignol E, Kobow K, Simonato M, Loeb JA, Grisar T, Gilby KL, Vinet J, Kadam SD, Becker AJ. WONOEP appraisal: new genetic approaches to study epilepsy. Epilepsia. 2014 Aug
New genetic investigation techniques, including next-generation sequencing, epigenetic profiling, cell lineage mapping, targeted genetic manipulation of specific neuronal cell types, stem cell reprogramming, and optogenetic manipulations within epileptic networks are progressively unraveling the mysteries of epileptogenesis and ictogenesis. This manuscript reviews recently published applications of these technologies in the study of epilepsy. The new genetic investigation techniques have considerably advanced our understanding of the molecular and epigenetic etiologies underlying various forms of epilepsy in humans and have provided unparalleled tools to dissect and study the impact of these genes on various components of the neural circuits involved in seizure generation. Furthermore, they are opening new avenues for the development of novel therapeutic approaches in epilepsy.
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