title: Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity.
abstract: Methylene blue (MB, methylthioninium chloride) is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Among its beneficial properties are its abilities to act as an antioxidant, to reduce tau protein aggregation and to improve energy metabolism. These actions are of particular interest for the treatment of neurodegenerative diseases with tau protein aggregates known as tauopathies. The present study examined the effects of MB in the P301S mouse model of tauopathy. Both 4 mg/kg MB (low dose) and 40 mg/kg MB (high dose) were administered in the diet ad libitum from 1 to 10 months of age. We assessed behavior, tau pathology, oxidative damage, inflammation and numbers of mitochondria. MB improved the behavioral abnormalities and reduced tau pathology, inflammation and oxidative damage in the P301S mice. These beneficial effects were associated with increased expression of genes regulated by NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE), which play an important role in antioxidant defenses, preventing protein aggregation, and reducing inflammation. The activation of Nrf2/ARE genes is neuroprotective in other transgenic mouse models of neurodegenerative diseases and it appears to be an important mediator of the neuroprotective effects of MB in P301S mice. Moreover, we used Nrf2 knock out fibroblasts to show that the upregulation of Nrf2/ARE genes by MB is Nrf2 dependent and not due to secondary effects of the compound. These findings provide further evidence that MB has important neuroprotective effects that may be beneficial in the treatment of human neurodegenerative diseases with tau pathology.
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Cliona
authors.initials: C
authors.lastname: Stack
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Shari
authors.initials: S
authors.lastname: Jainuddin
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ceyhan
authors.initials: C
authors.lastname: Elipenahli
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Meri
authors.initials: M
authors.lastname: Gerges
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Starkova
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.affiliation: Department de Medicina Experimental, Universitat de Lleida-IRBLLEIDA, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Jové
authors.affiliation: Department de Medicina Experimental, Universitat de Lleida-IRBLLEIDA, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.affiliation: Neurometabolic Diseases Laboratory-IDIBELL, Hospital Duran i Reynals, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, CIBERER, Spanish Network for Rare Diseases, ISCIII, Spain.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Launay
authors.affiliation: Neurometabolic Diseases Laboratory-IDIBELL, Hospital Duran i Reynals, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, CIBERER, Spanish Network for Rare Diseases, ISCIII, Spain, ICREA, Catalan Institution for Research and Advanced Studies, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Department of Pharmacology and Toxicology and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Navneet Ammal
authors.initials: NA
authors.lastname: Kaidery
authors.affiliation: Department of Pharmacology and Toxicology and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.affiliation: Hospital Kremlin Bicêtre, UMR 788, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Sud, Le Kremlin Bicêtre, France and.
authors.forename: Davide
authors.initials: D
authors.lastname: Tampellini
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA, IHU-A-ICM, Hospital Pitié-Salpêtrière, 75013 Paris, France mad2138@med.cornell.edu.
authors.forename: Magali
authors.initials: M
authors.lastname: Dumont
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008751:Methylene Blue / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D016875:tau Proteins; D008751:Methylene Blue