title: Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy.
abstract: We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy.
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy; Department of (Neuro)Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iori
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Iyer
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ravizza
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Beltrame
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Paracchini
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Milica
authors.initials: M
authors.lastname: Cerovic
authors.affiliation: Department of Pharmacy, University of Washington, Seattle, WA, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Hill
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.affiliation: Department of Biotechnologies and Life Sciences, Insubria University, Varese, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Molteni
authors.affiliation: Department of Biotechnologies and Life Sciences, Insubria University, Varese, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rossetti
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy; Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, United Kingdom.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Brambilla
authors.affiliation: Department of Pharmacy, University of Washington, Seattle, WA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Steve White
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, Amsterdam, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands; Stichting Epilepsie Instellingen (SEIN) Nederland and Epilepsy Institute in The Netherlands Foundation, The Netherlands. Electronic address: e.aronica@amc.uva.nl.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy. Electronic address: annamaria.vezzani@marionegri.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D000927:Anticonvulsants / Q000008:administration & dosage*; D002220:Carbamazepine / Q000494:pharmacology; D000458:Cyanobacteria; D004151:Dipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D006624:Hippocampus / Q000503:physiopathology; D007608:Kainic Acid; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000008:administration & dosage*; D009841:Oligonucleotides / Q000008:administration & dosage; D011897:Random Allocation; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062366:para-Aminobenzoates / Q000008:administration & dosage
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D004151:Dipeptides; C583355:IL1R1 protein, mouse; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D009841:Oligonucleotides; D053573:Receptors, Interleukin-1 Type I; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D062366:para-Aminobenzoates; C520022:belnacasan; D002220:Carbamazepine; D007608:Kainic Acid
keywords: Disease-modification; Epilepsy; Hyperexcitability; Neuroinflammation; Seizures