title: Influence of methylene blue on microglia-induced inflammation and motor neuron degeneration in the SOD1(G93A) model for ALS.
abstract: Mutations in SOD1 cause hereditary variants of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Pathophysiology of the disease is non-cell-autonomous, with toxicity deriving also from glia. In particular, microglia contribute to disease progression. Methylene blue (MB) inhibits the effect of nitric oxide, which mediates microglial responses to injury. In vivo 2P-LSM imaging was performed in ALS-linked transgenic SOD1(G93A) mice to investigate the effect of MB on microglia-mediated inflammation in the spinal cord. Local superfusion of the lateral spinal cord with MB inhibited the microglial reaction directed at a laser-induced axon transection in control and SOD1(G93A) mice. In vitro, MB at high concentrations inhibited cytokine and chemokine release from microglia of control and advanced clinical SOD1(G93A) mice. Systemic MB-treatment of SOD1(G93A) mice at early preclinical stages significantly delayed disease onset and motor dysfunction. However, an increase of MB dose had no additional effect on disease progression; this was unexpected in view of the local anti-inflammatory effects. Furthermore, in vivo imaging of systemically MB-treated mice also showed no alterations of microglia activity in response to local lesions. Thus although systemic MB treatment had no effect on microgliosis, instead, its use revealed an important influence on motor neuron survival as indicated by an increased number of lumbar anterior horn neurons present at the time of disease onset. Thus, potentially beneficial effects of locally applied MB on inflammatory events contributing to disease progression could not be reproduced in SOD1(G93A) mice via systemic administration, whereas systemic MB application delayed disease onset via neuroprotection.
authors.affiliation: Max-Planck-Institute for Experimental Medicine, Göttingen, Germany. Dibaj@em.mpg.de
authors.forename: Payam
authors.initials: P
authors.lastname: Dibaj
authors.forename: Jana
authors.initials: J
authors.lastname: Zschüntzsch
authors.forename: Heinz
authors.initials: H
authors.lastname: Steffens
authors.forename: Jörg
authors.initials: J
authors.lastname: Scheffel
authors.forename: Bettina
authors.initials: B
authors.lastname: Göricke
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Karim
authors.initials: K
authors.lastname: Le Meur
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Eike D
authors.initials: ED
authors.lastname: Schomburg
authors.forename: Clemens
authors.initials: C
authors.lastname: Neusch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D030801:Animals, Genetically Modified; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013997:Time Factors
chemical_list: D016207:Cytokines; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008751:Methylene Blue