Methylene blue for Alzheimer's disease

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What is Alzheimer’s

Alzheimer’s disease is a neurological disorder that negatively impacts the brain. In this brain disease, the brain cells die, resulting in memory loss and cognitive deterioration. It was named after Dr Alois Alzheimer, who identified the sickness for the first time in 1906. Loss of memory, language issues, and impulsive or unexpected behaviour are all common signs of Alzheimer’s disease.

In Alzheimer’s, it becomes difficult for information to readily move through various parts of the brain or between organs and the brain. Alzheimer’s disease is a chronic illness, which means that the characteristics worsen over time. Memory loss is a significant aspect, and it is usually one of the very first signs to appear.

Toxic alterations occur in the brain during the early stage of Alzheimer’s, particularly aberrant protein accumulations that generate amyloid plaques and tau tangles. Previously healthy Neurons that were initially healthy stop working, lose connections to neighbouring neurons and eventually die. Many additional complicated brain alterations are likely to contribute to Alzheimer’s disease as well. The impairment appears to begin in the two important areas of the brain – the hippocampus, and the entorhinal cortex. These parts are important for memory formation. Because more brain cells die, more areas of the brain become impacted and start to diminish. By the end stage of Alzheimer’s, deterioration spreads throughout the brain, and brain tissues are decreased substantially. The symptoms arise progressively over several months. If they appear for hours or days, the person requires medical treatment since it might lead to a severe stroke.

Some of the common symptoms of Alzheimer’s

People might have trouble processing new knowledge and retaining it. They might struggle with logic, complicated activities, and judgment.
Another characteristic is a breakdown in the communication between nerve cells in the brain.
The ability to identify people or things, as well as operate simple tools, may deteriorate.
For many people, a deterioration in non-memory elements of cognition, such as finding words while speaking, eyesight difficulties, and poor thinking or judgment, may indicate the illness is in its early stages.
The demeanour and behaviour might alter, such as being more disturbed, angry, or frightened than usual, losing interest in or enthusiasm for things they typically like and losing empathy.

How does Methylene Blue cure Alzheimer’s

According to experts at the University of Texas Health Science Center, an oral dosage of Methylene Blue can improve the reaction of brain areas that govern concentration and short-term memory.

Major cytopathology in the patients’ brains includes the failure of mitochondria and energy rate, which are presumably caused by the buildup of harmful amyloid-beta peptides. Methylene Blue boosts heme production and mitochondrial respiration, which is deficient in Alzheimer’s disease brains.

Methylene Blue has repeatedly been shown to be one of the most effective treatments for delaying maturity in human cells. One of Methylene Blue’s primary actions seems to be to improve mitochondrial activity. Methylene blue as a medication is approved by FDA for the treatment of methemoglobinemia, the control of UTIs in the aged, and as a surgical tissue dye

Usually, Methylene Blue is utilized in its original form as methylthioninium chloride; however, clinical testing in Alzheimer’s used both forms- reduced and oxidized Methylene Blue.

Oxidative stress is reduced in the accumulation of Alzheimer’s-like tau and -amyloid. Methylene blue decreases mitochondrial oxidant generation and free radical creation in vitro. It can also alter mitochondrial respiration downstream activities such as lipid oxidation, ATP synthesis, and ECM formation, contributing to improved neuronal oxidative metabolic capacity. Methylene blue may easily transition between oxidized and reduced states, acting as an electron carrier in the electron transport chain of the mitochondrial matrix. Additionally, methylene blue therapy increases cellular Oxygen consumption, ATP generation, and glucose absorption.

Mechanism of Methylene Blue on Alzheimer’s

The connection between Methylene Blue and Alzheimer’s disease has lately received more research interest because it has been proposed that Methylene Blue might halt the course of progress in Alzheimer’s. In fact, in addition to its well-known inhibitory effects on the cGMP pathway, Methylene Blue can influence a wide range of cellular and molecular processes associated with the course of Alzheimer’s disease. Currently, Methylene Blue has been proven to reduce the production of neurofibrillary tangles and plaques, as well as to partly restore the function of Mitochondria and cellular metabolic deficits.

Summary of all the research so far covering information from all the published research papers.

A lot of research has been done to see the effects of Methylene Blue in the treatment of Alzheimer’s disease. In a study performed by the researchers at the University of Texas Health Science Center, it was shown that Methylene blue induced a rise in reaction in the bilateral insular cortex, a brain area involved in the creation of new memories. Methylene blue treatment significantly enhanced short-term memory tests, with a 7% increase in accurate replies compared with the placebo group. This was most likely due to increased activity in the brain’s prefrontal cortex, which is responsible for processing the memories; the parietal lobe, involved in the processing of sensory information; and the occipital cortex, which is the visual processing centre of the brain.

In an article called Shedding Light on Alzheimer’s β-Amyloidosis: Photosensitized Methylene Blue Inhibits Self-Assembly of β-Amyloid Peptides and Disintegrates Their Aggregates, it was stated that Methylene Blue was a possible treatment for Alzheimer’s after TauRx Pharmaceuticals Ltd. revealed significant findings in phase II clinical research with mild-to-moderate Alzheimer’s disease patients.

In another article published on www.researchgate.net in June 2009, it was suggested that Methylene Blue contributed to slowing down the effects of the disease by reducing the production of amyloid plaques and neurofibrillary tangles as well as partly repairing the functioning of mitochondria and cellular metabolism. As a result, efforts have been made to create innovative Methylene Blue-based therapy approaches for Alzheimer’s.

An article with the title, ‘’Et Tu, Methylene Blue?’’ published on www.alzforum.org on 18th May 2015 it was stated that if Methylene Blue is administered in the early stages of Alzheimer then it can prevent the progression of the disease. It implied that Methylene Blue could be used as a preventive treatment for frontotemporal dementia. It was anticipated that the therapy would need to begin five years before people’s cognitive impairment.

According to research, a variety of variables other than genetics may have a role in the development and progression of Alzheimer’s. For instance, there is a lot more interest in the association between cognitive impairment and vascular disorders, including cardiovascular disease, strokes, hypertension, and diabetes, and obesity. Continuing research will assist us in determining if and how decreasing health risks for these disorders may also lessen the chance of Alzheimer’s.

Patents on Methylene blue and Alzheimer’s

Inhibition of tau-tau association, US7534786B2– Method for the treatment of Alzheimer’s disease, which method comprises administering to a subject in need thereof an effective amount of Methylene Blue, wherein the Methylene Blue is administered orally in a daily dosage of about 50 mg to about 700 mg

2. Materials and methods relating to protein aggregation in neurodegenerative disease US7893054B2 – Method for the treatment of Alzheimer’s Disease, which method comprises administering to a subject in need thereof a medicament composition comprising a diaminophenothiazine, wherein the diaminophenothiazine has been pre-reduced such that it is present in at least 80, 90, 95, or 99% reduced (leuco-) form.

Both of these patents have been filed by Wista Laboratories Ltd, a group company of TauRx Pharmaceuticals. The first patent has already expired while the second patent expires on 2022-01-15.

Results of clinical studies of Methylene blue in Alzheimer’s

Phase 2 Clinical trial

This study was conducted with 321 patients having mild or moderate Alzheimer’s. The purpose of this study was to determine the minimum effective dose of methylene blue, which was identified as 138 mg/ day.

As published on TauRx Pharmaceutiacals’ website, “In this study, rember® showed statistically significant benefit relative to placebo at 26 weeks on the primary psychometric scale (ADAS-cog), and showed an 80% reduction in the rate of clinical decline over 50 weeks relative to controls, with benefit sustained over 2 years in patients continuing with treatment at the 138 mg/day dose.”

The study also led to the development of another version of the medicine which was a stable reduced form of LMTM or Leucomethylthioninium that permitted direct absorption.

Phase 3 Clinical Trial

This program comprised of three separate studies – two clinical trials (TRx-005 and TRx-015) in Alzheimer’s disease and a further trial (TRx-007) in behavioural variant frontotemporal dementia (bvFTD; neurodegenerative orphan indication). All three studies were completed in 2016.

All three studies employed doses ranging from 150-250 mg/day against a low dose of 8 mg/day as an intended control.

The drug given at a higher dose failed to show any results in patients with mild to moderate Alzheimer’s. But the subset of the control group who were given a lower dose of 8 mg per day appeared to be effectively provided that it was employed as a monotherapy and the patients were not taking any other Alzheimer’s medication.

Based on the findings of the phase 3 trial, another study was conducted in which the researchers used the data collected from 1162 participants of the prior 3 trials. Their analysis implied that a low dose of 16 mg per day is effective in treating patients with mild to moderate Alzheimer’s.

As per Dr Clause Wischik who is the lead scientist in this research, lower dose is found to be more effective as it is in what is known to be in a reduced form, due to which it is more rapidly absorbed through the blood-brain barrier.

TauRx Pharmaceuticals is currently conducting another clinical trial for proving the efficacy of TRx0237 or LTMT at 16 mg/day and 8 mg/day in the treatment of subjects with Alzheimer’s Disease compared to placebo. The estimated primary completion date of this study is March 2022.

Hormetic Behaviour of Methylene Blue

It is quite possible that the phase 3 clinical trial failed to show results at a higher dosage of LMTM because of hormetic behaviour of methylene blue, the compound from which LMTM is derived. The low and high doses of methylene blue produce opposite effects. At lower doses, there is an equilibrium between in vivo methylene blue and leukomethylene blue which is they form a reversible oxidation-reduction system(electron cycling), and MBH2 can donate electrons to ETC complexes and oxygen, leading to enhanced energy metabolism and decreased superoxide formation.

In a research paper titled “Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue” the author concludes that this compound is frequently characterized by hormetic dose-response relationships at behavioural, physiological and biochemical levels. “Thus, at the doses spanning its hormetic zone, MB can increase these responses until they are 130–160% of control. For example, low doses of MB produce a maximum behavioural response with averages of approximately 140% of control. However, as MB dose is increased the response level diminishes, until it returns to control baseline response.”

Summing Up

Because Alzheimer’s disease and its symptoms are so complicated, no single drug or any particular treatment will ever be able to effectively treat it in all patients who are diagnosed with it. Despite this, scientists have made significant progress in the past few years to better understand the disease and create new medications and treatments, including numerous drugs currently in late-stage clinical studies.

Even though the use of methylene blue in treating Alzheimer’s has not received a green signal yet, it has still not been overruled and till the research continues so does the faith in methylene blue as a treatment for this disease.

The use of methylene blue in medicine is more than 120 years old, and it comes with a lot of available history about its use and impact. This makes the use of methylene blue as a medicine safe with an established safe dosage of 200 mg per day for adults. It is a well-defined compound in European pharmacopoeia and it is available in a high purity form from established API manufacturers like Macsen. (Note: – G6PD patients and SSRI and SNRI drug consumers cannot take this medicine)

Low dosages of methylene blue have been found to be effective against mitochondrial dysfunction. Methylene blue’s unique auto-oxidizing characteristic, as well as its pleiotropic actions on a variety of tissue oxidases, explain its powerful neuroprotective effects at low dosages. Low-dose methylene blue has a mechanistic function in enhancing memory and treating acute and chronic diseases characterized by increased oxidative stress, neurodegeneration, and memory impairment.

We don’t know whether methylene blue will be approved as a drug for Alzheimer’s but it has a great potential to become a supplement for improving mental health and antiaging.

Other articles on Methylene Blue:-

Disclaimer-

The information provided here is based on general knowledge, articles, research publications etc and we do not claim the authenticity of any of the information provided above. We do not claim or suggest/advise any medical, therapeutic, health or nutritional benefits of MB. We do not supply or promote our MB product for the applications which are covered by valid patents and which are not approved by the FDA.

Macsen Labs is a manufacturer and supplier of several grades of Methylene Blue such as:-

Macsen Labs group’s Methylene Blue Synthesis Process granted a patent from the Indian patent office

The Indian Patent Office granted a patent to Mr Achal Agrawal, CEO of Macsen Labs, Udaipur. The title of the patent is Novel Improved Method for Synthesis of Diaminophenothiazine Compounds and it concerns a novel process for synthesising the compound Methylthioninium Chloride or Methylene Blue. Macsen Labs has now achieved a unique position by this patent and from now nobody will be able to copy this process. Read more

Methylene Blue

Methylene blue for Alzheimer’s disease