TY - JOUR
T1 - Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity
AU - Stack, Cliona
AU - Jainuddin, Shari
AU - Elipenahli, Ceyhan
AU - Gerges, Meri
AU - Starkova, Natalia
AU - Starkov, Anatoly A.
AU - Jové, Mariona
AU - Portero-Otin, Manuel
AU - Launay, Nathalie
AU - Pujol, Aurora
AU - Kaidery, Navneet Ammal
AU - Thomas, Bobby
AU - Tampellini, Davide
AU - Flint Beal, M.
AU - Dumont, Magali
N1 - Funding Information:
This work was supported by the Tau Consortium (M.F.B.), NIH grant NS060885, Michael J Fox Foundation for Parkinson’s Disease Research, and Par Fore Parkinson’s (B.T.).
PY - 2014/7
Y1 - 2014/7
N2 - 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 10months of age.Weassessed 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.
AB - 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 10months of age.Weassessed 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.
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U2 - 10.1093/hmg/ddu080
DO - 10.1093/hmg/ddu080
M3 - Article
C2 - 24556215
AN - SCOPUS:84902953435
SN - 0964-6906
VL - 23
SP - 3716
EP - 3732
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 14
M1 - ddu080
ER -