This is a quick recap on the promising Alzheimer's disease drug methylene blue that was reviewed in a previous article last year. We now know that methylene blue is still currently undergoing testing in phase 2 clinical trials. However, it is still to be seen whether this drug will hold water for reversing Alzheimer's disease pathology; although this clinical study has been protracted for more two years with no apparent explanation.
On the bright side now. A study published July of last year performed by Dr. Oddo from the University of San Antonio Health Science Center in the journal of Brain Pathology showed that administration of methylene blue in a mouse model of Alzheimer's disease reduced Alzheimer's disease pathology and improved learning and memory. In brief, a dietary daily infusion of methylene blue decreased the number of tau and amyloid beta aggregates (the culprits for causing disease) in different regions of the brain and reversed cognitive decline as shown by memory and learning tests (water maze tests) . The 6 month old Alzheimer's disease mice were treated for 16 weeks with a 0.025% diet of weight by weight of methylene blue to diet food (25mg of MB per 100g of diet food). The mice showed no adverse signs of toxicity related to methylene blue nor any weight loss. This is analogous to a young adult taking about 250mg of methylene blue for 2- 4 years before any results are shown. Interestingly, the mechanism of action of methylene blue appeared to be the clearance of amyloid beta by increasing the proteolytic activity of enzymes that are involved in "chopping" up these aggregates in neurons (trypsin and chemotrypsin).
Finally, a recent study performed by Dr. Lima, soon to be published next month (February) in the journal of Neuroimage, showed that methylene blue protected against a model of amnestic mild cognitive impairment (Alzheimer's model) in rats . In brief, methylene blue administration in rats that were pretreated with sodium cyanide, a potent rat poison, protected against cyanide-induced brain lesion, cognitive impairment and hypometabolism and restored the network connectivity of neurons in the cyngulate gyrus (a region that is affected by Alzheimer's disease). Taken at face value, methylene blue is widely available for research use but not for clinical use and it is not expensive to buy. However, patient compliance may be low but the latter results show that maybe methylene blue could potentially be sold as supplements and patients can try-on-their-own treatment with prior doctor's approval.
References
1. Riha PD, Rojas JC, Gonzalez-Lima F. Beneficial network effects of methylene blue in an amnestic model. Neuroimage. 2011 Feb 14;54(4):2623-34. Epub 2010 Nov 16.
2. Medina DX, Caccamo A, Oddo S. Methylene Blue Reduces Abeta Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity. Brain Pathol. 2010 Jul 27. [Epub ahead of print]
More on methylene blue
A series of breakthroughs and discoveries last year have neurologists and medical doctors excited over the possibility that an ancient, simple and common household drug may actually hold the cure for not only Alzheimer's disease but for other neurodegenerative diseases such as Parkinson's disease and Amyotrophic lateral sclerosis.
Methylene blue, an ancient common dye with a multitude of applications, is currently being tested in phase II clinical trials in Alzheimer's disease patients. Rember, a drug that has been developed by TauRX Therapeutics, contains methylene blue as one of its active ingredients and is currently being tested in Phase II clinical trials. Indeed, pilot and phase I studies have shown that methylene blue significantly reverses cognitive decline seen in Alzheimer's disease patients with mild dementia and improves quality of life when compared to a placebo control groups. Specifically, the group treated with a high dose of Rember for several weeks showed about an 80% more improvement in cognitive function compared to the placebo treated group.
This groundbreaking report last year is significant since no single Alzheimer's disease drug to date has had a significant impact in the treatment of this devastating neurodegenerative disease. Indeed, Rember has proven to cause about a two to threefold increase in reversing Alzheimer's disease symptoms compared to Aricept, an acetylcholinesterase inhibitor, which only causes modest to no significant improvement.
However, many leading scientists that perform research int he field of Alzheimer's disease are optimistically cautious about the future of methylene blue for the treatment of Alzheimer's disease given the issues of toxicity, low oral availability and low blood brain barrier penetrance. Although it has been postulated that methylene blue may not cure Alzheimer's disease, any drug that reverses symptoms, improves quality of life, delays neurodegeneration, and saves billions of dollars in hospice care and clinical care costs is a huge stride in progress towards curing Alzheimer's disease.
It is important to note that the chemical formulation of methylene blue in Rember is proprietary and is significantly different than methylene blue used in other medical applications.
Other non-clinical research has enhanced the credence to the notion that methylene blue may be a wonder drug for not just treating Alzheimer's disease but other neurodegenerative diseases. For instance, many tissue culture studies have shown that methylene blue can reversed the aggregation of tau, a protein that forms toxic aggregates called senile neurofibrillary tangles in Alzheimer's disease brain tissue, in different neuronal cell lines and enhance neuronal survival.
Moreover, methylene blue can destroy and dissolve toxic aggregates formed by amyloid beta, another protein that is aggregated in Alzheimer's disease, in neuroblastoma cell lines and improves neuronal survival. Interestingly, other research suggests that methylene blue may be a general anti-protein aggregate buster since other tissue culture studies show that this wonder compound also inhibits the aggregation of TDP-43, a protein that forms the major component of inclusions aggregates in amyotrophic lateral sclerosis and in frontotemporal degeneration. In other word, methylene blue may have other medical applications to treat many other neurodegenerative diseases.
Remarkably, the biological effects of methylene blue does is not limited to its anti-protein aggregate activity but has been shown to improve the function of mitochondria in neurons.
Mitochondria are the essential energy centers for neurons that provide the necessary energy to neurons to carry out its essential functions such survival, neurotransmitter release and maintenance of axons and dendrites. Mitochondrial dysfunction is one of the main etiologies that underlie neurodegeneration in Alzheimer's disease. Free radicals spewed by mitochondria in neurons seem to be elevated in neurons of Alzheimer's disease patients which contribute to degeneration of hippocampal and cortical neurons. There is a decrease in mitochondrial respiration (complex I and IV activities), alterations in the normal structure of mitochondria and impaired mitochondrial function in Alzheimer's disease patients. Remarkably, methylene blue is able to enhance mitochondrial function, delay cellular senescence (aging) by enhancing the activity of antioxidants and promotes survival under basal conditions in fibroblasts . In other words, this study shows that methylene blue acts as an anti-oxidant by sequestering free radicals released by mitochondria and somehow restores mitochondrial respiration at the level of complex I and IV.
These remarkable results show that methylene blue may possibly delay dementia and cognitive decline in Alzheimer's disease patients by improving mitochondrial function in neurons and by acting as a plaque and tangle buster by dissolving toxic tau and amyloid beta aggregates.
Final thoughts-
There is significant headway into finding alternative therapies and potential cures for treating Alzheimer's disease. The fact that Rember is being tested in phase II clinical trials as a promising elixir for Alzheimer's disease suggests that other drugs with similar chemical structures such as green polyphenols found in green tea might have similar promising effects.
The drawback with Rember is that very high doses of this drug is necessary to achieve the medical benefits. This may be a concern since methylene blue can cause annoying toxic side effects such as anemia, local necrosis at the site of injection, vomiting, and bladder irritation as seen with other dye compounds.
It is true that testing existing compounds in the pipeline that are already in the market for other medical applications has its advantages such as saving a lot of money in synthesizing and testing hundreds of other drugs. On the other hand, chemically altering the structure of methylene blue to allow it to penetrate the blood brain barrier and reduce its toxicity will be a challenge for biomedical scientists in the near future.
About Methylene blue
Methylene blue is a soluble blue/green aromatic chemical compound that has a multitude of biological and chemical uses. Some of the most notable uses of methylene blue includes preventing and reversing cyanide poisoning, treating malaria, carbon monoxide poisoning and for the treatment of methemoglobinemia, a condition in which hemoglobin is oxidized by other drugs.
Methylene blue is also commonly used as a DNA dye for histopathological studies of human tissue in diagnostic laboratories and for staining cells prepared in tissue culture studies at research labs. Methylene blue is even used for educational purposes in universities and colleges. For instance, methylene blue is used as a redox indicator in chemistry labs to teach students the basic concepts of oxidation and reduction!
What is Alzheimer's disease?
In brief, Alzheimer's disease is an age dependent, relentless, chronic and incurable neurodegenerative disease characterized by a progressive loss of neurons of the hippocampus and the cortex leading to a progressive decline in cognitive function. The pathological hallmarks of AD is characterized by the presence of protein aggregates located in the axons, dendrites and in cell bodies of neurons. These protein aggregates have been termed neurofibrillary tangles, protein aggregates mainly composed of hyper-phosphorylated tau, and senile plaques, protein aggregates mainly composed of amyloid beta. The accumulation of these protein aggregates have been associated with neuronal loss as shown by tissue culture studies in multiple neuronal cell lines and in mouse models of Alzheimer's disease.
Generally, the age of onset of this disease is around 60-65 years of age, although there are familial manifestations of the disease which can lead to a much earlier age of onset. This disease affects an estimated 26.6 million people worldwide. To this date, there is no cure for the disease and only supportive treatment is available which includes administering patients with a cocktail of antioxidants, NMDA and glutamate receptor inhibitors to slow down degeneration of neurons and cognitive and psychotherapy (validation therapy) to slow memory loss.
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Comments
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" It is important to note that the chemical formulation of methylene blue in Rember is proprietary and is significantly different than methylene blue used in other medical applications."
Good article.
But why would you feel it necessary to add this falsehood? First, if the formulation is "proprietary" then how would you know that it is significantly different? Are you privy to the proprietary formula? Of course not. This statement was made either with intention to mislead or else without thinking about its logic..
Methylene blue is methylene blue. Plenty of studies have been done with the simple chemical that can be found at the aquarium store and the memory enhancement results are significant enough to cast suspicion on any claims that a proprietary formula is necessary for results.
Second, dose is everything. With MB, they are finding that extremely low doses works best. Because a high dose takes a long time to work does not mean that a higher dose would take a shorter time. With MB, it seems as if mcg doses are key to faster and better results.
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