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: Cliona Stack, Shari Jainuddin, Ceyhan Elipenahli, Meri Gerges, Natalia Starkova, Anatoly A Starkov, Mariona Jové, Manuel Portero-Otin, Nathalie Launay, Aurora Pujol, Navneet Ammal Kaidery, Bobby Thomas, Davide Tampellini, M Flint Beal, Magali Dumont
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 14 Pg. 3716-32 (Jul 15 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24556215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• NF-E2-Related Factor 2
• Neuroprotective Agents
• tau Proteins
• Methylene Blue

Topics

• Animals
• Behavior, Animal (drug effects)
• Cell Line
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Methylene Blue (administration & dosage, pharmacology)
• Mice
• Mice, Transgenic
• Mitochondria (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Neuroprotective Agents (administration & dosage, pharmacology)
• Oxidative Stress (drug effects)
• Sex Factors
• Signal Transduction (drug effects)
• Tauopathies (drug therapy, pathology)
• tau Proteins (genetics, metabolism)