title: Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems.
abstract: Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis.
authors.affiliation: Group of Neuroplasticity and Regeneration, Institut de Neurociències and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Herrando-Grabulosa
authors.affiliation: Anaxomics Biotech SL, Barcelona, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Mulet
authors.affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Catalonia, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Anaxomics Biotech SL, Barcelona, Catalonia, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Mas
authors.affiliation: Group of Neuroplasticity and Regeneration, Institut de Neurociències and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
authors.affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aloy
authors.affiliation: Anaxomics Biotech SL, Barcelona, Catalonia, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Coma
authors.affiliation: Group of Neuroplasticity and Regeneration, Institut de Neurociències and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Barcelona, Spain.
authors.forename: Caty
authors.initials: C
authors.lastname: Casas
mesh_terms: D000465:Algorithms; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use*; D003198:Computer Simulation; D004359:Drug Therapy, Combination; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology / Q000627:therapeutic use*; D008962:Models, Theoretical; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D002867:Chromones; D018696:Neuroprotective Agents; C047681:pranlukast; D015767:Mefloquine