Twele F, Bankstahl M, Klein S, Römermann K, Löscher W. The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. Neuropharmacology. 2015 Aug;95:234-42.
The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists, such as NBQX or perampanel, exert anti-seizure activity in diverse animal models of partial and generalized seizures. Furthermore, NBQX treatment following neonatal seizures was recently reported to block the development of later-life spontaneous seizures in rats, indicating a marked antiepileptogenic effect. This prompted us to evaluate whether NBQX is also capable of preventing or modifying development of spontaneous seizures in an adult mouse model of difficult-to-treat mesial temporal lobe epilepsy, the intrahippocampal kainate model. When mice were treated over three days after kainate-induced status epilepticus with NBQX, using a protocol similar to that used in the neonatal model, no effect on development or frequency of spontaneous recurrent seizures (SRS) was found. However, once SRS were established, they were suppressed by both NBQX and perampanel, but not phenytoin. These data suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.
Williamson A, Ferro M, Leleux P, Ismailova E, Kaszas A, Doublet T, Quilichini P, Rivnay J, Rózsa B, Katona G, Bernard C, Malliaras GG. Localized Neuron Stimulation with Organic Electrochemical Transistors on Delaminating Depth Probes. Adv Mater. 2015 Jun 30. Epub ahead of print.
Many types of electrodes are used to record brain activity, but also to stimulate neurones, as in Parkinson’s disease and epilepsy. Clinical electrodes are invasive, and poorly biocompatible. In addition, it is not easy to perform both stimulations and recordings. In this study, Organic electrochemical transistors are integrated on depth probes to achieve localised electrical stimulation of neurones. The probes feature a mechanical delamination process which leaves only a 4 μm thick film (100% biocompatible) with embedded transistors inside the brain. This considerably reduces probe invasiveness and correspondingly improves future brain-machine interfaces. The transistors can be switched from a recording mode to a stimulation mode without altering their performance. The stimulation can be very localised, activating small populations of neurones.
Mishto M, Raza ML, de Biase D, Ravizza T, Vasuri F, Martucci M, Keller C, Bellavista E, Buchholz TJ, Kloetzel PM, Pession A, Vezzani A, Heinemann U. The immunoproteasome β5i subunit is a key contributor to ictogenesis in a rat model of chronic epilepsy. Brain Behav Immun. 2015 Jun 1. pii: S0889-1591(15)00149-X.
The immunoproteasome (IP), the inducible isoform of the catalytic unit of the ubiquitin/proteasome system, is involved in pathophysiological functions related to immunity and inflammation. The expression of the beta5i key catalytic subunit of the IP is induced in the epileptogenic foci surgically resected from patients with pharmaco-resistant seizures. We show that the β5i immuno-subunit is induced in experimental epilepsy, and its selective pharmacological inhibition significantly prevents, or delays, 4-aminopyridine-induced seizure-like events in acute rat hippocampal/entorhinal cortex slices. The recent availability of selective β5i subunit inhibitors opens up novel therapeutic opportunities for seizure inhibition in drug-resistant epilepsies.
Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A, Oppenheim H, Ardizzone C, Becker A, Frigerio F, Vezzani A, Buckwalter MS, Huguenard JR, Friedman A, Kaufer D. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood–brain barrier dysfunction. Neurobiol Dis. 2015 Jun;78:115-25.
Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. In this study we demonstrate that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE.
Williamson A, Rivnay J, Kergoat L, Jonsson A, Inal S, Uguz I, Ferro M, Ivanov A, Sjöström TA, Simon DT, Berggren M, Malliaras GG, Bernard C. Controlling Epileptiform Activity with Organic Electronic Ion Pumps. Adv Mater. 2015 May;27(20):3138-44.
Many potentially potent anti-epileptic drugs failed in the clinic because: i) they could not reach the brain (i.e. not passing the brain blood barrier); ii) they had deleterious side effects, affecting the function of “healthy” regions; iii) they were toxic in the periphery (e.g. in the liver). In this paper, the authors demonstrate an organic electronic ion pump that can deliver pure molecules directly in the regions of interest to control epileptic activity, without affecting the function of neighbouring regions, thus solving all the aforementioned problems. The device is minimally invasive and biocompatible, which opens the way to deliver already designed potent drugs where and when they are needed.
Gorter JA, van Vliet EA, Aronica E. Status epilepticus, blood–brain barrier disruption, inflammation and epileptogenesis. Epilepsy Behav. 2015 May 6. Epub ahead of print
Over the last 15 years, attention has been focused on dysfunction of the cerebral vasculature and inflammation as important players in epileptogenic processes, with a specific emphasis on failure of the blood–brain barrier (BBB). Here, we discuss how the BBB is disrupted as a consequence of status epilepticus and how this BBB breakdown may be involved in epileptogenesis.
Gorter JA, van Vliet EA, Lopes da Silva FH. Which insights have we gained from the kindling and post-status epilepticus models? J Neurosci Methods. 2015 Apr 1. pii: S0165-0270(15)00120-X. Epub ahead of print.
In this paper, we review different aspects of the kindling model with emphasis on experiments in the rat. Next, we review characteristic properties of the post-status epilepticus (SE) models and compare the neuropathological, electrophysiologicaland molecular differences between kindling and post-SE epilepsy models. Finally, we shortly discuss the advantages and disadvantages of these models.
Lévesque M, Avoli M, Bernard C. Animal models of temporal lobe epilepsy following systemicchemoconvulsant administration. J Neurosci Methods. 2015 Mar 10. pii: S0165-0270(15)00091-6.
In this paper, we review the kainic acid and pilocarpine models of temporal lobe epilepsy, assessing status epilepticus in different species and strains. We describe the general events occurring during the latent and chronic periods, including neuropathological modifications. We also discuss the effect of anti-epileptic drugs on spontaneous seizures.
van Vliet ES, Aronica E, Gorter JA. Blood-brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol. 2015 Feb;38:26-34.
The blood–brain barrier (BBB) is a dynamic and complex system which separates the brain from the blood. It helps to maintain the homeostasis of the brain, which is essential for normal neuronal functioning. BBB function is impaired in several neurological diseases, including epilepsy in which it may lead to abnormal and excessive neuronal firing. In this review we will discuss how BBB dysfunction can affect neuronal function and how this can lead to seizures and epilepsy. We will also summarize new therapies that aim to preserve or restore BBB function in order to prevent or reduce epileptogenesis.
Welch ME, Doublet T, Bernard C, Malliaras GG and Ober CK. A glucose sensor via stable immobilization of the GOx enzyme on an organic transistor using a polymer brush. J Polym Sci A Polym Chem. 2014, 53:372–377.
This paper demonstrates a fast and sensitive organic sensor able to measure extracellular glucose levels. An organic transistor is grafted with nanobrushes carrying the enzyme glucose oxidase, directly measuring the concentration of glucose.
Jirsa VK, Stacey WC, Quilichini PP, Ivanov AI, Bernard C. On the nature of seizure dynamics. Brain. 2014 Aug;137(Pt 8):2210-30.
In this paper, we show that the onset and offset of partial seizures follow simple mathematical properties, which are universal across species (from flies to Human) and across brain regions. We introduce a slow variable that pushes network over seizure threshold, and show possible biophysical correlates.
Book chapter
Vezzani, A, Lang B, Aronica E. Immunity and Inflammation in Epilepsy. Epilepsy: The Biology of a Spectrum Disorder Chapter 10(Noebels and Holmes editors), in press.
This chapter reports the available evidence on the activation of the innate and adaptive branches of the immune system, and the related inflammatory processes, in epileptic disorders, and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures as well as in the associated neuropathology and comorbidities. Major challenges in this field remain a better understanding the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.
Meeting of the UK Epilepsy Society London, 20 February 2015: Title: MicroRNAs in the pathogenesis of epilepsy: New opportunities in epilepsy research?. E. Aronica.
Dutch League Against Epilepsy symposium, 11 March 2015, Amsterdam, The Netherlands. Title: Can the blood-brain barrier be a target for anti-epileptogenic treatment? E.A. van Vliet.
11th Göttingen Meeting of the German Neuroscience Society 2015. 18-21 March 2015. Title: Astrocyte immune responses in epilepsy. E. Aronica.
Third BBBNedwork meeting, 20 March 2015, Leiden, The Netherlands. Title: In vivo models with impaired blood-brain barrier. E.A. van Vliet.
International epilepsy symposium, 27 March 2015, The Netherlands. Title: Blood-brain barrier dysfunction, seizures and epilepsy. E.A. van Vliet.
Presentation at Antiepileptic drug device trials XIII, Turberry Isle, Aventura, Florida, USA, 13-15 May 2015, Title: Preclinical assessment to screen therapies for disease modification. A. Vezzani.
Invited lecture at ADD Program Symposium on Therapy Development in the Era of Team Science and Big Data, Park City, Utah. 17-20 May 2015. Title: State of Animal Models – Redux. W Löscher.
Presentation at ADD symposium: Therapy development in the era of team science and big data, Park City, Utah, USA, 17-20 May 2015. Title: miR146a-based therapy against neuroinflammation has anti-ictogenic and disease-modifying effects in murine models of seizures and epilepsy. A. Vezzani.
Sander K., Gendron T., Yiannaki E., Cybulska K., Kalber T., Lythgoe M., Årstad E. Functionalized Triarylsulfonium Salts for Aromatic [18F]Fluorination of Drug-like Small Molecules. J Label Compd Radiopharm 2015, 58, S4, DOI: 10.1002/jlcr.3302_1. Oral presentation at the 21st International Symposium on Radiopharmaceutical Sciences, University of Missouri, Columbia, MO, USA – May 26-31, 2015.
Gendron T., Sander K., Cybulska K., Gray V., Årstad E. Dibenzothiophene sulfonium salts as leaving groups for aromatic [18F]fluorination – exemplified by highly efficient direct labelling of the mGluR5 PET tracer [18F]FPEB. J Label Compd Radiopharm 2015, 58, S8, DOI: 10.1002/jlcr.3302_1. Oral presentation at the 21st International Symposium on Radiopharmaceutical Sciences, University of Missouri, Columbia, MO, USA – May 26-31, 2015.
Spring Hippocampal Research Conference. 7-11 June 2015 Taormina, Sicily. Title: The role of astrocytes in epilepsy: “Inflammation and miRNAs: miR-146a, a key regulator of astrocyte-mediated inflammatory response in epilepsy. E. Aronica.
