Introduction:
Methylene blue or methylthioninium chloride is a remarkable compound in the history of pharmacology and chemotherapeutics. Methylene blue was the first phenothiazine compound developed, and it has active biological properties which have been under investigation for over 120 years. It was first developed to stain and inactivate certain microbes that, became the first synthetic chemical tested in human patients, which had been demonstrated as effective in malaria treatment. That led to a great interest in using Methylene blue for numerous therapeutic applications, from microbiology to psychiatry.
For example, Methylene blue is a therapeutic dye with antimicrobial activity, supravital staining and diagnostic histopathological uses, blood staining activity, medicinal photosensitizer action, cancer chemotherapeutic uses, and psychoactive uses in dementia and psychosis. Currently, some of the most important clinical uses of methylene blue include the therapy of methemoglobinemia, septic shock, encephalopathy, and ischemia.
Methylene Blue and Alzheimer’s Disease
Alzheimer’s disease is a common form of dementia in older adults. It causes problems with memory, thinking, and behavior. The disease is characterized by abnormal protein deposits in the brain, including β-amyloid plaques and neurofibrillary tangles. These deposits lead to the loss of brain cells, especially in the cholinergic system, which affects memory and cognitive function. Methylene Blue has positively affected various neurotransmitter systems, mitochondrial function, and the formation of amyloid plaques and neurofibrillary tangles in the brain.
How Does Methylene Blue Help Alzheimer’s Patients
a. Cognitive enhancement
Methylene Blue quickly crosses the blood-brain barrier. It improves mitochondrial efficiency and respiration, acts as an antioxidant, and increases brain cell lifespan, improving memory and mood. Methylene Blue improves memory by increasing brain cell respiration, or how the brain cell utilizes oxygen. It increases ATP production to provide more cellular energy for better overall brain function, including cognition, mood, and memory. Accordingly, it prevents aging-related and disease-related memory loss, especially in treating acute or chronic conditions associated with mitochondrial dysfunction in humans.
A low methylene blue dose was thought to oxidize hemoglobin, increasing the oxygen-carrying capacity of red blood cells and inducing a counterintuitive retrograde enhancement of memory. Methylene Blue has a direct interaction not only with the oxygen-carrying system but also with the tissues consuming oxygen. Increases in brain cytochrome oxidase and oxygen consumption in relation to memory enhancement have been indeed demonstrated after the administration of methylene blue.
Methylene Blue acts as a neuroprotective agent and can enhance cognitive function. Glutamatergic transmission plays an important role in learning and memory, while Methylene Blue is well known to improve cognitive function in animal models. Here, we see a multimodal action of Methylene Blue addressing both the pathology and symptomology (cognitive decline) of Alzheimer’s disease.
b. Tau protein aggregation
Methylene Blue has been found to have positive effects on Alzheimer’s disease. It inhibits the clumping together of harmful proteins called β-amyloid while promoting the formation of fibrils. This is important because the clumping of tau proteins is associated with the loss of nerve cells and the severity of dementia in Alzheimer’s patients. Methylene Blue inhibits the formation of these tau protein tangles, specifically targeting certain domains of the protein. Overall, there is evidence suggesting that methylene blue can help address both the primary features of Alzheimer’s disease, neurofibrillary tangles, and beta-amyloid plaques.
Studies on Methylene Blue and Alzheimer’s
Despite the intensive research on Alzheimer’s disease and the depth to which we understand the cell biology and biochemistry of β-amyloid, a therapy or prevention strategy for Alzheimer’s disease remains elusive. The absence of a definite molecular mechanism to explain the neurotoxicity of β-amyloid is a key obstacle to developing effective therapies to treat Alzheimer’s disease. Drugs currently available to treat Alzheimer’s disease patients (e.g., blocking NMDA glutamate receptors, acetylcholine esterase inhibitors) are targeted at treating only the symptoms of Alzheimer’s disease, and their efficacy is also limited. The efficiency of these drugs progressively declines as the disease progresses, indicating that they do not alter the underlying neurodegenerative mechanism of β-amyloid.
Clinical studies have shown that Methylene Blue may slow the cognitive decline in Alzheimer’s disease by inhibiting β-amyloid protein oligomerization and inhibiting aggregation and filament formation of the microtubule-associated protein tau. Also, the inhibition of tau aggregation by Methylene Blue has been demonstrated in cell and animal models.
Another clinical trial in the United States investigated the effects of methylene blue in healthy aging, mild cognitive impairment, and Alzheimer’s disease, with the primary outcomes being working and episodic memory task fMRI and response as a change from baseline with treatment for 2 or 12 weeks.
In 2015 a study reported that 321 patients with mild or moderate disease were treated with Methylene Blue in clinical trials. Based on the cognitive subscale of the Alzheimer’s Disease Scale, 138 mg daily had a moderate effect after six months.
The brain is extremely sensitive to oxygen and glucose deprivation due to its high energy demands. Ischemia, or cessation of blood flow, to the brain, can be either focal or global. Therapeutic hypothermia is the only currently indicated intervention to prevent Global cerebral ischemia-induced cell death. Adding Methylene Blue to therapeutic hypothermia managed to rescue neuronal cell death and behavioral outcomes after extended global cerebral ischemia. Therefore, combination therapy is likely the key to maximizing the beneficial effects of Methylene Blue, especially considering the wide range of scope and variety of ischemic brain injuries, stroke in particular. If Methylene Blue proves successful in treating ischemic brain injury, focal or global, it could open up effective treatment in diverse healthcare settings due to its pervasive distribution worldwide.
With its low side effect profile, there lies the possibility that Methylene Blue delivered prophylactically or at the early stages of Parkinson’s Disease may prevent the progression of the disorder. Finally, the MAO inhibitor properties of Methylene Blue may provide added benefits to an ongoing regimen of levodopa. The close association of the profile of Methylene Blue’s mitochondrial effects and the myopathy present in Parkinson’s Disease seems promising, highlighting the necessity of applying MB to the various Parkinson’s Disease chemical and genetic animal models.
Recent evidence indicates that Methylene Blue could modulate the migration of murine adult neural stem cells in a cell migration assay. Much more evidence is necessary to draw a solid conclusion on the effect and role of Methylene Blue in promoting adult neurogenesis and mitochondrial health in old age. If validated, Methylene Blue may serve as a multifaceted tool for preserving cognition and quality of life for the elderly population, a demographic vital in an aging society.
Methylene Blue should be investigated with renewed enthusiasm in years to come. If these results are validated in future human studies, Methylene Blue could be a versatile agent that could improve the health of patients suffering from the burden of neurodegenerative disorders and brain injury, giving them and their loved ones relief and a better quality of life.
Why it is better to take Methylene Blue as compounded capsules.
Stability: Methylene Blue is a water-soluble dye that can be unstable in some forms, such as liquid or injectable solutions. Compounding pharmacies can create more stable capsules that are less likely to break down.
Dosage: Methylene Blue is a powerful drug and can be toxic in high doses. Compounding pharmacies can create capsules with precise dosages tailored to the patient’s needs.
Taste: Methylene Blue has a strong, unpleasant taste. Capsules can help to mask the taste and make it easier to take the medication.
Convenience: Capsules are easy to take and can be taken with or without food. They are also more portable than liquid or injectable solutions.
References
- Behavioral, Physiological, and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue
- Methylene blue and Alzheimer’s disease
- Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue
- Methylene blue and its analogs as antidepressant compounds
- Methylene Blue in the Treatment of Neuropsychiatric Disorders
- Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations
- Clinical effectiveness and prospects of methylene blue: A systematic review
- From Mitochondrial Function to Neuroprotection—an Emerging Role for Methylene Blue
