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Drugs Based on Methylene Blue Enter the Treatment Pipeline
Wikipedia image of Methylene Blue
Researchers led by Dr. Leslie Thompson, a neurobiologist at University of California–Irvine, have identified a possible treatment for Huntington’s disease, the dye methylene blue. Methylene blue has been previously reported to slow progression and improve cognition in Alzheimer’s patients in a Phase IIb study. It has good bioavailability and low toxicity and it crosses the blood barrier, making it a promising candidate as a drug affecting the central nervous system. It is an FDA-approved treatment for methemoglobinemia, a disease where hemoglobin is unable to effectively carry out its task of releasing oxygen to body tissues. This disease can be genetic or caused by exposure to certain chemicals. In the case of the former, patients take methylene blue for a lifetime. Methylene blue was first used as a treatment for malaria in 1891 so there is a long history of medical use.
The researchers studied methylene blue in a cell model, drosophila model and a mouse model of HD, the R6/2 mouse. They also looked at methylene blue’s effect on the HD protein itself, outside of a cell. They found that when methylene blue was introduced to N-terminal fragments of the HD protein, it blocked the aggregation of monomers (single peptides), oligomers (tiny, hard to see aggregates), and fibrils (small, ribbon-like aggregates) into the large insoluble aggregates. The greatest effect was achieved with monomers.
Methylene blue decreased oligomeric and insoluble HD protein aggregate formation and increased survival time in primary cortical cells from a rat model of HD.
Methylene blue was able to reduce neurodegeneration in a drosophila model of HD when fed to larva but not after maturity. Treating the drosophila at the larval stage reduced the number of aggregates by 87 percent and the ones that did form were smaller.
In the R6/2 mice, methylene blue delayed the characteristic loss of coordination and balance as measured by rotarod performance. Levels of insoluble HD protein were decreased in the treated mice as compared to the untreated mice. In addition, levels of the neuroprotective brain-derived neurotrophic factor (BDNF), known to be decreased in HD patients, were increased in the mice given methylene blue.
What is the mechanism by which methylene blue exerts its positive effects in these models? The researchers focus on its effect on aggregation of the HD protein, also noting that the increase in BDNF may be helpful as well.
In 1997, large aggregates of the HD protein were first discovered in the R6/2 mice and then in the brains of patients who had died with HD. An early hypothesis was that these aggregates were a major pathology in the disease. While the large aggregates are certainly not normal, more recent research suggests that it is the soluble monomeric or oligomeric aggregates which are toxic rather than the large inclusions originally found. Methylene blue’s effect on monomers and oliogomers suggests that this is a viable mechanism for reducing HD pathology.
Methylene blue was tested in a zebrafish model of Huntington’s disease in 2010 by a team of researchers led by Dr. Hans van Bebber. While methylene blue was effective in preventing visible aggregates, it was not effective in slowing disease onset or preventing toxicity. Dr. Thompson and her team note that this model uses a fragment of the HD protein which lacks the adjoining proline region found in the full length protein. It seems likely that its absence accounts for the negative results which contrast with the current study since another researcher reports that methylene blue was ineffective in a cell model of HD which also lacked the proline region.
Methylene blue may exert positive effects by other mechanisms as well. It should also be noted that methylene blue also exerts.antioxidant and electron-shuttling effects in the mitochondria. In a blog written by Promega Company scientists, Anupama Gopalakrishnan points out that methylene blue will enter the mitochondria (energy factories) of the cell where it acts as an antioxidant, decreases the production of reactive oxidative species, increases cell respiration, and prevents cell death from oxidative stress. Oxidative damage is a known pathology in Huntington’s disease.
Dr. Hani Atamna and colleagues from the The Commonwealth Medical College, found that when methylene blue was fed to mice over time it “increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37–70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium.” They also found that “the activity of complex IV in brain of old mice was doubled upon treatment with methylene blue for three months.” They argue that the enhancement of mitochondrial function might be one of the ways in which methylene blue exerts positive effects in Alzheimer’s.
Another team of researchers offer a different perspective about methylene blue and mechanism in Alzheimer’s. Working with a mouse model of AD which shows increasing levels of the tau and the amyloid beta proteins as well as increasing cognitive defects with age, they found improvement in learning and memory in the group receiving methylene blue. They found no decrease in levels of the tau protein but did find a decrease in the amyloid beta protein. This protein appeared to being produced at typical disease levels so they examined changes in protein clearance. Methylene blue appears to increase the ability of the proteasome to clear away the protein by enhancing its chymotrypsin-and trypsin-like activities.
What is next:
"This study shows promise pre-clinically and follow-up studies are needed in a more representative mouse model that expresses the full-length Huntingtin protein and allows more study of the disease’s neurogenerative properties," says Dr. Albert La Spada, a neurogeneticist at the University of California–San Diego.
Dr. Thompson agrees and adds, "Because of existing knowledge of methylene blue and the fact that it’s not harmful to humans, I would hope that progress toward clinical trials could go relatively quickly."
In addition, HDSA will be following any subsequent trials of methylene blue based drugs in Alzheimer’s or other neurodegenerative diseases.
The history of methylene blue as a potential treatment for Alzheimer’s disease:
Looking at the progress of methylene blue as a potential treatment in Alzheimer’s may tell us something about how this compound could move through the HD pipeline of potential treatments.
The Alzheimer’s community was electrified by a report from the 2008 International Conference on Alzheimer’s Disease that Alzheimer’s patients in a Phase IIb study showed an improvement in cognition after 6 months and a slowing of disease progression by 81 percent over a one year period. The research was carried out by Dr. Claude Wischik and his team at the University of Aberdeen. Dr. Wischik, Dr. K.M. Seng, the University of Aberdeen and investors formed TauRx to develop tau inhibitors as treatments for neurodegenerative diseases.
The researchers used a version of methylene blue trademarked as Rember. Recently, TauRx has reported on its website that it has developed a second generation tau aggregation inhibitor also based on methylene blue. They claim that the chemically optimized inhibitor, called LMTX, has better tolerability and bioavailability. They are now planning a Phase III trial in the U.S. and Europe for mild and moderate Alzheimer’s and researching the possibility that the drug might treat Parkinson’s patient. Just as this article was being written, the company announced an international trial for Frontotemporal dementia, also called Pick’s disease. Huntington’s disease is not mentioned on the website but the company may be interested now that the research by Dr. Thompson and her colleagues has been reported.
References: Hani Atamna and Raj Kumar. “Protective Role of Methylene Blue in Alzheimer’s Disease via Mitochondria and Cytochrome c Oxidase.” Journal of Alzheimer’s Disease 20 (2010) S439–S452.
Anupama Gopalakrishnan. “Dyed Cells Live Longer?” Promega Connections Blog 29 August 2012. http://promega.wordpress.com/2012/08/29/dyed-cells-live-longer/#more-16231
Trisha Gura. “Hope in Alzheimer’s fight emerges from unexpected places.” Nature Medicine 2008 Sep;14(9):894.
David X. Medina, Antonella Caccamo, and Salvatore Oddo. “Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity.” Brain Pathology 2011 March; 21(2): 140–149.
Kathleen Raven. “Laboratory Dye Repurposed against Protein Clumps found in Huntington’s Disease.” Nature Medicine Blog 07 Aug 2012 http://blogs.nature.com/spoonful/2012/08/laboratory-dye-repurposed-against-protein-clumps-found-in-huntingtons-disease.html
*Emily Mitchell Sontag, Gregor P. Lotz, Namita Agrawal, Andrew Tran, Rebecca Aron, Guocheng Yang, Mihaela Necula, Alice Lau, Steven Finkbeiner, Charles Glabe, J. Lawrence Marsh, Paul J. Muchowski, and Leslie M.Thompson. “Methylene Blue Modulates Huntingtin Aggregation Intermediates and Is Protective in Huntington's Disease Models.” The Journal of Neuroscience 2012 Aug 8;32(32):11109-11119.
TauRx website. http://www.taurx.com/index.aspx
Frauke Van Bebber, Dominik Paquet, Alexander Hruscha, Bettina Schmid, and Christian Haas. “Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish.” Neurobiology of Disease Vol 30:5 September 2010, Pages 265–271.
Claude M. Wischik, Peter Bentham, Damon J. Wischik, Kwang Meng Seng. “Tau aggregation inhibitor (TAI) therapy with rember arrests disease progression in mild and moderate Alzheimer’s disease over 50 weeks.” Alzheimer’s and Dementia Volume 4, Issue 4, Supplement, Pages A1-A8, T1-T880 (July 2008).
- Marsha L. Miller, Ph.D., September 12, 2012