Methylene Blue - used for over a century in Psychiatry, also handy for your fish tank

According to the packaging:-

Effective against a range of fungal and bacterial infections

•          Increases the oxygen-carrying capacity of fish

•          Can be used as an antiseptic directly onto wounds

•          For use in tropical and cold water aquariums

 

Our reader Dragos recently let us all know about his success with very low doses of Methylene Blue (MB).  I think this came as a surprise to many, but actually there is nothing new about using this old pigment as a therapy in psychiatry.  Much is known about its modes of action.

 

What is Methylene Blue?

In 1876, German chemist Heinrich Caro synthesized methylene blue (MB) for the first time in history.  It was used as a dye for textiles. Around the same time, it was found that MB is capable of staining cells by binding to their structures, in addition, sometimes inactivating bacteria. This discovery prepared the way for biological or medical studies related to MB. Numerous scientists applied it to a variety of animal and bacterial studies, importantly Paul Ehrlich introduced it to humans in 1891 as an anti-malarial agent.

I was interested to see why it is used in aquariums, in particular the reference to increases the oxygen-carrying capacity of fish.

Methemoglobinemia (MetHb) is a rare blood disorder that affects how red blood cells deliver oxygen throughout your body.

A common way to treat  MetHb  in humans is to reduce methemoglobin levels using  Methylene blue (MB). Another common treatment, not surprisingly, is to give oxygen.

If you want to increase oxygen levels in the fish in your aquarium you put MB in the water.

More oxygen in your blood would improve exercise endurance meaning you would delay the point at which your mitochondria become unable to keep producing ATP efficiently.

I did some investigation and there is indeed a trend towards people using methyl blue to improve their sporting performance. It is mocked in some newspapers because it makes your tongue turn blue. It makes for good pictures on Instagram.     

The effect will be similar to those long distance cyclists who take beetroot juice, but the mechanism is different.

Be aware that just like beetroot may dye what comes out of your body bright red, MB may give you a hint of blue.

  

Improved Mitochondrial Function

One of the known effects of Methylene Blue (MB) is on the mitochondria.

In numerous papers it has been discussed how MB improves brain mitochondrial respiration.

In neurological disorders such as Alzheimer’s disease, traumatic brain injury, depression, stroke, Parkinson’s disease and some autism, mitochondria contribute to the disorder through decreased energy production and excessive production of reactive oxygen species (ROS).

This subject does get rather complex but in short methylene blue is able to perform alternative electron transport, bypassing parts of the electron transport chain.

In autism terms this means that some people diagnosed with a lack of Complex 1, 2, 3 or 4 in their mitochondria, might want to pay particular attention to how Methylene Blue might be helpful.

Improved mitochondrial function is another reason why sportsmen might want to use MB to enhance their performance.

As we have seen with other enhancing drugs like the Russian Meldonium, the US Diamox and the new US super ketone products, the military do end up using these products.  If you see a picture of a navy seal with a blue tongue you will know where it came from!

 

Methylene Blue inhibits Monoamine Oxidase (MAO)

MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two types of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.

Methyl blue is a reversible selective MAO-A inhibitor and so has antidepressant properties (it gives you more feel good serotonin). This interesting drug has several other pharmacological actions, including inhibition of nitric oxidase synthase (NOS), and guanylate cyclase and so its antidepressant properties should not be solely ascribed to inhibition of MAO-A. 

Inhibition of neuronal nitric oxide synthase and soluble guanylate cyclase prevents depression-like behaviour in rats exposed to chronic unpredictable mild stress

Beyond treating depression MAOIs (Monoamine oxidase inhibitors) have been found to be effective in the treatment of panic disorder, social phobia, mixed anxiety disorder and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder, and Obsessive Compulsive Disorder (OCD).

MAOIs appear to be particularly effective in the management of bipolar depression.

Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study

Background: Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects.

Aims: We conducted a double-blind crossover study of a low dose (15 mg, 'placebo') and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine.

Method: Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning.

Results: The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects.

Conclusions: Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.

 

Methylene Blue activates oxidative stress response genes via Nrf2

One of the antioxidant effects of MB is activation of the redox switch Nrf2.  In the paper below it is also mentioned that MB has a beneficial against tau proteins. Amyloid and tau proteins clog up the brain in Alzheimer’s and as a result MB has been proposed as a therapy for dementia. 

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity

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.

 

MB to treat inflammation and pain via sodium ion channels and iNOS

MB abates inflammation by suppressing nitric oxide production, and ultimately relieves pain in arthritis and colitis.  

MB suppresses the iNOS/NO-mediated inflammatory signaling by directly downregulating inducible NO synthase (iNOS).

Nitric oxide (NO) is a free radical which, in reactions with various molecules causes multiple biological effects, some good and some harmful.

It is produced by a reaction involving one of three enzymes iNOS, eNOS and nNOS.  i = inducible, n = neuronal and e = endothelial

iNOS is a major downstream mediator of inflammation.

eNOS is very helpful because it can widen blood vessels and so reduce blood pressure and increase blood flow.

nNOS is found in the brain and the peripheral nerve system where it has several important functions.  

MB may impede pain transmission by dampening neuronal excitability elicited by voltage-gated sodium channels (VGSCs).  You would then think that in people with seizures due to malfunctioning sodium channels, MB might be beneficial; for example Nav1.1 in Dravet syndrome. 

Methylene Blue Application to Lessen Pain: Its Analgesic Effect and Mechanism

Methylene blue (MB) is a cationic thiazine dye, widely used as a biological stain and chemical indicator. Growing evidence have revealed that MB functions to restore abnormal vasodilation and notably it is implicated even in pain relief. Physicians began to inject MB into degenerated disks to relieve pain in patients with chronic discogenic low back pain (CDLBP), and some of them achieved remarkable outcomes. For osteoarthritis and colitis, MB abates inflammation by suppressing nitric oxide production, and ultimately relieves pain. However, despite this clinical efficacy, MB has not attracted much public attention in terms of pain relief. Accordingly, this review focuses on how MB lessens pain, noting three major actions of this dye: anti-inflammation, sodium current reduction, and denervation. Moreover, we showed controversies over the efficacy of MB on CDLBP and raised also toxicity issues to look into the limitation of MB application. This analysis is the first attempt to illustrate its analgesic effects, which may offer a novel insight into MB as a pain-relief dye. 

Nicotinic acetylcholine receptors

The modulation of nicotinic acetylcholine receptors (nAChRs) has been suggested to play a role in the pathogenesis of various neurodegenerative diseases. 

MB acts as a non-competitive antagonist on α7 nAChRs.

Well known drugs that act in a similar way include the Alzheimer’s drug Memantine and Ketamine. Recall that intranasal Ketamine has been used in autism. 

Substances  with the opposite effect include nicotine, choline and of course

Amyloid beta, the marker of Alzheimer's disease.

Note that some people need to block α7 nAChRs and some people need to activate them. 

Methylene blue inhibits the function of α7-nicotinic acetylcholine receptors

FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications

A list of the serotonergic psychiatric medications that can interact with methylene blue can be found here. 

• Methylene blue can interact with serotonergic psychiatric medications and cause serious CNS toxicity.
• In emergency situations requiring life-threatening or urgent treatment with methylene blue (as described above), the availability of alternative interventions should be considered and the benefit of methylene blue treatment should be weighed against the risk of serotonin toxicity. If methylene blue must be administered to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped, and the patient should be closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine [Prozac] was taken), or until 24 hours after the last dose of methylene blue, whichever comes first.
• In non-emergency situations when non-urgent treatment with methylene blue is contemplated and planned, the serotonergic psychiatric medication should be stopped to allow its activity in the brain to dissipate. Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of methylene blue treatment. Fluoxetine (Prozac), which has a longer half-life compared to similar drugs, should be stopped at least 5 weeks in advance.
• Treatment with the serotonergic psychiatric medication may be resumed 24 hours after the last dose of methylene blue.
• Serotonergic psychiatric medications should not be started in a patient receiving methylene blue. Wait until 24 hours after the last dose of methylene blue before starting the antidepressant.
• Educate your patients to recognize the symptoms of serotonin toxicity or CNS toxicity and advise them to contact a healthcare professional immediately if they experience any symptoms while taking serotonergic psychiatric medications or methylene blue.

Conclusion 

Rather surprisingly, this therapy from the fish tank may have wide ranging effects on the autistic brain and in those with dementia, bipolar etc.

Possible benefits might include:

·        Improved production of ATP (energy) in the brain

·        Reduced oxidative stress in the brain

·        Reduced nitrosative stress

·        Reduced inflammation

·        Improved mood (due to increased serotonin)

·        Improved memory and cognitive function

·        Reduction in obsessive behaviors

In one of the papers, they comment that “methylene blue modulates functional connectivity in the human brain”.

It seems to work for Dragos.  You can also see that people on Reddit use it for issues like ADHD. 

 

Note the FDA warning:

Do not combine Methylene Blue with serotonergic psychiatric medications, because of the risk of serotonin syndrome (i.e., serotonin toxicity).

Repurposing Autism Drugs to treat Alzheimer’s – Bumetanide for APOE4 Alzheimer’s and Clemastine for all Alzheimer’s

The Gladstone Center for Translational Advancement was formed in 2017, and focuses on drug repositioning; repurposing already-approved drugs for new uses and clinical trials, to speed up (and lower the cost of) drug development.

 

Our neurologist reader Eszter commented recently on the overlap between experimental therapies for Alzheimer’s and those for autism. She was mentioning GHK-Cu, which is a naturally occurring peptide in our bodies that looks interesting in the research on both Alzheimer’s and Parkinson’s.  There will be post on GHK-Cu, but this is a potential therapy that would require injections, so it has a big drawback

In the early days of this blog we looked at the repurposing of Alzheimer’s drugs like Memantine, Donepezil and Galantamine for some autism.

Roll forward a few years and we now have quite a handful of autism drugs in the portfolio. Today we look again at how some of these autism drugs can be repurposed for Alzheimer’s.

We have come full circle.

In a previous post we saw that Fenamate NSAIDs, like Ponstan, reduce the incidence of Alzheimer’s.  Only a low dose seems to be required for Alzheimer's and this drug is extremely cheap in countries like Greece. A low dose seems to have a broad effect on autism.  All in all very interesting, I believe.

We saw that Agmatine improves cognitive dysfunction and prevents cell death in a Streptozotocin-Induced Alzheimer rat model.

We saw that the ketone BHB inhibits inflammasome activation to attenuate Alzheimer's disease pathology.

I have mentioned the interest to repurpose Verapamil to treat Huntington’s disease, via its effect on autophagy, but there is also interest to use it in Alzheimer’s.

Repurposing verapamil for prevention of cognitive decline in sporadic Alzheimer’s disease

Today we will look at why Bumetanide and Clemastine may be beneficial in Alzheimer’s. 

 

A quick summary of Alzheimer’s Disease 

Alzheimer’s disease features prominently plaques (amyloid plaques) and fibers (tau tangles) that are visible within the brain.

It is thought that inhibiting the aggregation and accumulation of amyloid plaques and tau in the brain is the key to treating Alzheimer’s Disease.

We did see that that the red pigment in beetroot has been shown to block the formation of amyloid plaques and no prescription is required for that superfood.

In addition, we know that there is reduced glucose uptake across the blood brain barrier via the GLUT1 and GLUT3 transporters.  In effect the brain is left starving. There is also impaired insulin signalling within the brain, this led to the idea of intranasal insulin as a treatment.  The insulin dependent glucose transporter GLUT4 plays a central role in hippocampal memory processes, and reduced activation of this transporter may underpin the cognitive impairments seen in Alzheimer’s disease and more generally in those who develop insulin resistance. (more insulin inside the brain, please)

We also did look at the recently discovered lymphatic drainage system of the brain. It was seen that this waste clearing system is impaired in Alzheimer’s and perhaps some autism. This then takes us back to the autophagy process within the brain, where cellular waste is collected. It is thought that autophagy itself is impaired in autism. Collecting and disposing of brain garbage does not function as it should.

Over a decade or so, the brain gradually shrinks away and loses functions.  I think in reality Alzheimer’s initially develops slowly, years before diagnosis.

The currently prescribed drugs do not alter the course of the disease and often provide only minimal benefit. Donepezil increases acetylcholine concentrations at cholinergic synapses and upregulates nicotinic receptors. Memantine blocks NMDA receptors.  Much more appears to be possible.

This is an autism blog so let’s be aware of the research on the overlaps with Alzheimer’s. 

Alzheimer’s protein turns up as potential target for autism treatments 

Lowering the levels of a protein called tau, best known for its involvement in Alzheimer’s disease, eases autism-like traits in mice, according to a study published today in Neuron.

Tau regulates a gene called PTEN, according to a 2017 study4. PTEN accounts for 2 to 5 percent of autism cases and is known to modulate the PI3K pathway; without it, the pathway becomes overactive, in some cases leading to autism.

Mucke’s team found that knocking out PTEN in neurons blocks the effect of lowering tau on the mice’s behaviors. 

Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

 Bumetanide for APOE4 Alzheimer’s?

Certain genes can increase the risk of developing dementia, including Alzheimer’s disease. One of the most significant genetic risk factors is a form of the apolipoprotein E gene called APOE4. About 25% of people carry one copy of APOE4, and 2 to 3% carry two copies. APOE4 is the strongest risk factor gene for Alzheimer’s disease, although inheriting APOE4 does not mean a person will definitely develop the disease.

The APOE gene comes in several different forms, or alleles. APOE3 is the most common and not believed to affect Alzheimer’s risk. APOE2 is relatively rare and may provide some protection against Alzheimer’s disease.

The reason APOE4 increases Alzheimer’s risk is not well understood. The APOE protein helps carry cholesterol and other types of fat in the bloodstream. Recent studies suggest that problems with brain cells’ ability to process fats, or lipids, may play a key role in Alzheimer’s and related diseases.

Regular readers of this blog will be familiar of the remarkable effects of statin drugs. So from the mention of cholesterol we take a brief diversion to see how people who start taking statins before older age get yet another benefit.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830056/#:~:text=Additionally%2C%20statins%20could%20reduce%20dementia,in%20Alzheimer's%20disease%20%5B70%5D.

 

"Additionally, statins could reduce dementia risk by directly affecting Alzheimer’s disease pathology. A study in transgenic mice models of Alzheimer’s disease found that atorvastatin reduced Aβ formation [69], and atorvastatin can attenuate some the damage from neuroinflammation in Alzheimer’s disease [70].

Much of the evidence supporting statins in the prevention of dementia and AD are in persons exposed to statins at mid-life as opposed to late life. This suggests that statins benefits may be limited to the vascular prevention stage of AD and dementia. "

 

Back to Bumetanide.

 

The easy to read article:-

 

Can an Already Approved Drug Treat Alzheimer’s Disease?  

An Alternative Approach to Drug Discovery 

Developing new, targeted drugs for complex conditions like Alzheimer’s disease is a notoriously long and expensive process. In 2017, with the goal of bringing safe treatments to patients more quickly, Huang launched the Gladstone Center for Translational Advancement to repurpose FDA-approved drugs for new uses.

 

Huang’s approach centers around the idea that patients with Alzheimer’s disease may have different underlying causes of neurodegeneration, and therefore, the efficacy of specific treatments may differ among patients—a strategy called precision medicine. However, in the large clinical trials required for new drugs, it can be hard to pinpoint whether a drug is effective in only a subpopulation of the patients.

 

Therefore, the research team used a computational approach to identify unique gene expression profiles (or the level to which genes are turned on or off) associated with Alzheimer’s disease in brain tissues from specific subgroups of patients. They then screened a database of existing drugs to find the ones most likely to reverse the altered gene expression profiles in each subgroup.

 

In the new study, the researchers first analyzed a publicly available database of 213 brain samples from people with and without Alzheimer’s disease, including people with different versions of a gene called APOE, the major genetic risk factor for the disease.

The team identified nearly 2,000 altered gene expressions in the brains of people with Alzheimer’s disease. While roughly 6 percent of the altered genes were similar between people with different APOE versions, the vast majority of them were unique to people with specific combinations of the APOE3 or APOE4 versions, the latter conferring the highest genetic risk of Alzheimer’s disease.

The researchers next queried a database of more than 1,300 existing drugs to look for those able to change the altered gene expressions they had identified for subgroups of Alzheimer’s patients. They zeroed in on the top five drugs that might reverse the altered gene expressions found in Alzheimer’s patients carrying two copies of the high-risk APOE4 version.

 

“This unbiased approach allowed us to find which drugs might be able to flip the altered gene expression associated with APOE4-related Alzheimer’s disease back to the normal state,” says Alice Taubes, PhD, lead author of the study and former graduate student in Huang’s lab at Gladstone and co-mentored by Marina Sirota at UCSF. “It gave us important clues in solving the puzzle of which drugs could be effective against APOE4-related Alzheimer’s disease.”

 

After looking at the known mechanisms and previous data on the drugs in their top-five list, the researchers homed in on bumetanide, a diuretic that reduces extra fluid in the body caused by heart failure, liver disease, and kidney disease. Bumetanide is known to work by changing how cells absorb sodium and chloride—both important not only for maintaining appropriate levels of water throughout the body, but also for electrical signaling of neurons in the brain.

 

Huang and his team tested the effect of bumetanide on mice genetically engineered to have human APOE genes. Mice with two copies of the human APOE4 version typically develop learning and memory deficits around 15 months of age—the equivalent of roughly 60 years in humans. But when the researchers treated the mice with bumetanide, they no longer developed such deficits. In addition, the drug rescued alterations in electrical brain activity that can underlie these cognitive deficits.

 

The scientists also studied a second mouse model of Alzheimer’s disease, in which two copies of APOE4 coexist with amyloid plaques—a major pathological sign of Alzheimer’s disease in the brain. In these mice, bumetanide treatment decreased the number of amyloid plaques and restored normal brain activity.

 

Lastly, when the researchers studied the effect of the drug on human neurons derived from skin cells of Alzheimer’s patients carrying the APOE4 gene, they found that bumetanide reversed the gene expression changes associated with the disease.

 

… the researchers evaluated two large electronic health record databases—one from UCSF containing information on 1.3 million patients seen from 2012 through 2019, and another from the Mount Sinai Health System covering 3.9 million patients seen from 2003 through 2020. They narrowed in on more than 3,700 patients who had taken bumetanide and were over the age of 65, and compared them to patients of similar age and health who had taken different diuretic drugs. Strikingly, the patients who had taken bumetanide were 35 to 75 percent less likely to be diagnosed with Alzheimer’s disease.

 

 

 

The full paper:-

 

It gets a bit heavy, so just skip through it.

 

Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease

 

The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD. Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD. 

Bumetanide exposure is associated with a significantly lower AD prevalence in individuals over the age of 65. We hypothesized that, if bumetanide is efficacious against AD, we would observe a lower prevalence of AD diagnosis in individuals exposed to bumetanide than in a matched control cohort of individuals over the age of 65 years. To test this hypothesis in humans, we analyzed two independent EHR databases (Fig. 7a). One is an EHR database from the University of California at San Francisco (UCSF), which contains complete medical records for 1.3 million patients from outpatient, inpatient and emergency room encounters as part of clinical operations from June 2012 to November 2019. The UCSF EHR database was filtered using the medication order table for patients on the drug of interest, and we found 5,526 patients who had used bumetanide (other names, Bumex or Burinex). Among them, 1,850 patients (1,059 men (57.2%) and 791 women (42.8%)) were over the age of 65. The other EHR database was from the Mount Sinai Health

 

Fig. 7 | Bumetanide exposure is associated with a significantly lower AD prevalence in individuals over the age of 65 in two independent EHR databases.

Bootstrapped χ2 tests40 confirmed a significantly lower AD prevalence in bumetanideexposed individuals than that in non-bumetanide-exposed individuals in both EHR databases (Fig. 7b,c). Together, these data suggest that bumetanide may be effective in preventing AD in individuals over the age of 65 years, warranting further tests in prospective human clinical trials.

 

Discussion 

This study represents an attempt to apply a precision medicine approach to computational drug repurposing for AD in an APOE genotype-directed manner. The efficacy of a top predicted drug, bumetanide, for APOE4 AD was validated in vivo in both aged APOE4-KI (without Aβ accumulation) and J20/E4-KI (with Aβ accumulation) mouse models of AD for rescue of electrophysiological, pathological or behavioral deficits. Importantly, by leveraging real-world data, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two independent EHR databases, suggesting the potential effectiveness of bumetanide in preventing AD in humans.

Bumetanide exposure is associated with a significantly lower AD prevalence in individuals over the age of 65 in two independent EHR databases.

 

Clemastine for Alzheimer’s 

The research suggests multiple possible benefits from the use of the cheap antihistamine Clemastine in Alzheimer’s.

 

Clemastine Attenuates AD-like Pathology in an AD Model Mouse via Enhancing mTOR-Mediated Autophagy

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with limited available drugs for treatment. Enhancing autophagy attenuates AD pathology in various AD model mice. Thus, development of potential drugs enhancing autophagy may bring beneficial effects in AD therapy. Methods: In the present study, we showed clemastine, a first-generation histamine H1R antagonist and being originally marketed for the treatment of allergic rhinitis, ameliorates AD pathogenesis in APP/PS1 transgenic mice. Chronic treatment with clemastine orally reduced amyloid-β (Aβ) load, neuroinflammation and cognitive deficits of APP/PS1 transgenic mice as shown by immunohistochemistry and behavioral analysis. We further analyzed the mechanisms underlying the beneficial effects of clemastine with using the combination of both in vivo and in vitro experiments. We observed that clemastine decreased Aβ generation via reducing the levels of BACE1, CTFs of APP. Clemastine enhanced autophagy concomitant with a suppression of mTOR signaling. Conclusion: Therefore, we propose that clemastine attenuates AD pathology via enhancing mTORmediated autophagy.

 

Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse 

Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.

  

Reversing Alzheimer's disease dementia with clemastine, fingolimod, or rolipram, plus anti‐amyloid therapy

A few anti‐amyloid trials offer a slight possibility of preventing progression of cognitive loss, but none has reversed the process. A possible reason is that amyloid may be necessary but insufficient in the pathogenesis of AD, and other causal factors may need addressing in addition to amyloid. It is argued here that drugs addressing myelination and synaptogenesis are the optimum partners for anti‐amyloid drugs, since there is much evidence that early in the process that leads to AD, both neural circuits and synaptic activity are dysfunctional. Evidence to support this argument is presented. Evidence is also presented that clemastine, fingolimod, and rolipram, benefit both myelination and synaptogenesis. It is suggested that a regimen that includes one of them plus an anti‐amyloid drug, could reverse AD. 

Note that Rolipram is a selective PDE4 inhibitor that never made it to use in humans. Roflumilast is very similar and counts as an autism drug in this blog, alongside Pentoxifylline, which is a non-selective PDE inhibitor (if affects more than just PDE4). 

Conclusion

It looks like if you were an enlightened neurologist treating autism you would have the drugs needed to make a fair crack at treating, or preventing, Alzheimer’s.  Unfortunately, once they are established, you are not going to cure either disease; nonetheless, fully treating autism will carry forward the person further than their ABA therapist would ever have dreamed possible. Treating Alzheimer's successfully will depend on when you start, best to start as soon as the signs appear on an MRI or CT scan, not a few years later.

Prevention is better than cure; indeed an older person’s multipurpose Polypill looks to be in order. This could go beyond the usual cardiovascular concerns and include prevention/mitigation of dementia and diabetes (e.g. statin, low dose ponstan, verapamil and a mix of betanin, spermidine, agmatine with ALA or NAC)

Just because you might carry the APO4 gene does not mean you will develop Alzheimer’s, but it is a good reason to take steps to prevent it.

There is a long list of factors that increase the incidence/severity of autism, so there are is an equal number of steps that can be taken to reduce it.

The gene expression study showed that Bumetanide has wide ranging effects within the brain that counter the defects found in APO4 mice and humans who have developed Alzheimer’s.  This suggests that bumetanide’s effects go well beyond blocking the NKCC1 cotransporter.  This may explain why some bumetanide responders with autism have a paradoxical reaction to GABA agonists, like benzodiazepines, and some people do not. They are receiving different beneficial effects.

We will look at the anti-inflammatory benefits of bumetanide suggested in very recent Chinese research in the next post.  This might provide biomarkers for likely responders. 

You might have thought that clemastine would not be good for dementia, because it is anticholinergic, as are many antihistamines and even drugs commonly given to older people like Nexium. The neurotransmitter acetylcholine is good for cognition and it has been suggested that depleting it might lead to dementia.

It looks like our off-label MS drugs, clemastine, Ibudilast and Roflumilast are going to be good for dementia, not to forget our new reader Bob and his Pentoxifylline.

It is notable that Gladstone Center for Translational Advancement exists. There are clearly very many existing drugs that can be repurposed to treat all kinds of medical issues. I keep discovering more, which is good for me. Bob discovered Pentoxifylline, which is good for him and his patients.  Other people are free to make their own choices.