title: Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model.
abstract: Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the involvement of both the innate and adaptive immune responses in ALS pathogenesis. In particular, abnormal TLR4 signaling in pro-inflammatory microglia cells has been related to motoneuron degeneration leading to ALS. In this study the effect of small molecule TLR4 antagonists on in vitro ALS models has been investigated. Two different types of synthetic glycolipids and the phenol fraction extracted from commercial extra-virgin olive oil (EVOO) were selected since they efficiently inhibit TLR4 stimulus in HEK cells by interacting with the TLR4·MD-2 complex and CD14 co-receptor. Here, TLR4 antagonists efficiently protected motoneurons from LPS-induced lethality in spinal cord cultures, and inhibited the interleukine-1β production by LPS-stimulated microglia. In motoneurons/glia cocultures obtained from wild type or SOD1 G93A mice, motoneuron death induced by SOD1mut glia was counteracted by TLR4 antagonists. The release of nitric oxide by LPS treatment or SOD1mut glia was also inhibited by EVOO, suggesting that the action of this natural extract could be mainly related to the modulation of this inflammatory mediator.
authors.affiliation: Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, Milano, Italy. Electronic address: massimiliano.depaola@marionegri.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: De Paola
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy.
authors.forename: Stefania E
authors.initials: SE
authors.lastname: Sestito
authors.affiliation: Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mariani
authors.affiliation: Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, Milano, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Memo
authors.affiliation: Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, Milano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fanelli
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, Milano, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Freschi
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa, 19, Milano, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Calabrese
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy. Electronic address: francesco.peri@unimib.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D018920:Coculture Techniques; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000069463:Olive Oil / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D000069463:Olive Oil; D010636:Phenols; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; D013482:Superoxide Dismutase
keywords: Amyotrophic lateral sclerosis (ALS); Extra virgin olive oil; Inflammation; Microglia; Motoneuron; TLR4