Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse models.
Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial function, to reduce reactive oxygen species, to clear aggregates of toxic proteins, and to act as a nitric oxide synthase inhibitor. These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice. Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS. The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score, and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A) mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.
Research Centre of CHUQ and Department of Psychiatry and Neurosciences, Laval University, 2705 Laurier Boulevard, QC, Canada G1V 4G2.
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D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008094:Lithium / Q000008:administration & dosage; D008751:Methylene Blue / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D000975:Antioxidants; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008094:Lithium; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008751:Methylene Blue