Circular Dichroism Spectroscopy Identifies the β-Adrenoceptor Agonist Salbutamol As a Direct Inhibitor of Tau Filament Formation in Vitro

You can ask your doctor what pieces of the kitchen sink they are throwing at preventing Alzheiners/dementia before clinical stuff is proven. 

Is this earlier research enough for your doctor to use?

Can An Anti-Asthma Drug Rejuvenate the Brain? montelukast January 2016 

A Decades-Old Asthma Drug Has Reversed Brain Damage From Dementia in Mice - zileuton July 2018

 

Or is your doctor using one of these to prevent dementia? 

1.  The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline by Dale Bredesen 

 

2.  A Real Alzheimer's Prevention Program from The University of California

 

3. I'm a Brain Doctor, and This Is What I Do to Prevent Alzheimer's December 2018 

 

4. Reversing the Alzheimer’s Catastrophe April 2007 

The latest here:

Circular Dichroism Spectroscopy Identifies the β-Adrenoceptor Agonist Salbutamol As a Direct Inhibitor of Tau Filament Formation in Vitro

• David J Townsend*
, 
• Barbora Mala
, 
• Eleri Hughes
, 
• Rohanah Hussain
, 
• Giuliano Siligardi
, 
• Nigel J. Fullwood
, and 
• David A. Middleton

Cite this: ACS Chem. Neurosci. 2020, XXXX, XXX, XXX-XXX

Publication Date:June 10, 2020

https://doi.org/10.1021/acschemneuro.0c00154

Copyright © 2020 American Chemical Society

Abstract

Potential drug treatments for Alzheimer’s disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilization and cell death. Here, a small library of structurally diverse compounds was screened in vitro for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 screened compounds. Subsequently, we tested chemically similar phenolamine drugs from the β-adrenergic receptor agonist class, using conventional circular dichroism spectroscopy, thioflavin T fluorescence, and transmission electron microscopy. Two compounds, salbutamol and dobutamine, used widely in the treatment of respiratory and cardiovascular disease, impede the aggregation of tau in vitro. Dobutamine reduces both the rate and yield of tau filament formation over 24 h; however, it has little effect on the structural transition of tau into β-sheet structures over 24 h. Salbutamol also reduces the yield and rate of filament formation and additionally inhibits tau’s structural change into β-sheet-rich aggregates. Salbutamol has a good safety profile and a half-life that facilitates permeation through the blood–brain barrier and could represent an expediated approach to developing AD therapeutics. These results provide the motivation for the in vivo evaluation of pre-existing β-adrenergic receptor agonists as a potential therapy for AD through the reduction of tau deposition.

Study shows asthma drug salbutamol's potential as Alzheimer's treatment

You'll want your doctor to keep you informed of this, so ask her/him how they are keeping up with research that survivors need to know about.  The answer will tell you about your hospital's competence. If neither of the following never made it to your hospital you need to start the firings with the board of directors.

Can An Anti-Asthma Drug Rejuvenate the Brain? montelukast January 2016 

A Decades-Old Asthma Drug Has Reversed Brain Damage From Dementia in Mice - zileuton July 2018

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

5. Parkinson’s Disease May Have Link to Stroke March 2017 

The latest here:

Study shows asthma drug salbutamol's potential as Alzheimer's treatment

MedicalXpress Breaking News-and-Events|July 2, 2020

A new study reveals that the common asthma drug salbutamol may offer potential as a treatment for Alzheimer's disease.

Alzheimer's disease is the most common form of dementia, affecting 47 million people worldwide and its prevalence is expected to triple to more than 130 million cases by 2050.

No effective treatments that cure the disease or slow down its progression have been discovered. However, this new early-stage study has revealed that repurposing an existing drug, salbutamol, offers significant potential as a low cost and rapid response option.

Extensive analytical in-vitro experiments conducted by the research team show that salbutamol is effective at reducing the accumulation of insoluble fibers of the tau protein—which is found in the brains of people with Alzheimer's disease. These microscopic fibers accumulate into neurofibrillary tangles and can cause neuron destabilization, brain cell death, and are a key characteristic of the disease's progression.

Much Alzheimer's disease research has focused on the build-up of amyloid plaques, caused by misfolding of the amyloid-β protein. However, because of disappointing results from numerous therapies targeting Aβ aggregation, more attention is shifting towards tau.

This study, led by researchers at Lancaster University, used a new automated 'high throughput' screening approach to study the structure of the misfolding tau protein with a special analytical technique called 'Synchrotron Radiation Circular Dichroism' (SRCD) at Diamond Light Source, the UK national synchrotron light source in Oxfordshire. With this powerful technique they were able to look at a selection of more than 80 existing compounds and drugs simultaneously to determine their effectiveness at preventing the formation of tau fibrils.

This method confirmed the compound epinephrine, more commonly known as adrenaline, was effective at stabilizing the tau proteins and preventing the formation of tau tangles. However, our bodies do not easily absorb epinephrine and it rapidly gets metabolized, so the scientists then looked at a range of readily available compounds with similar chemical structures. This search revealed four current drugs as possible candidates—etamivan, fenoterol, dobutamine and salbutamol.

Etaminvan and fenoterol were found to have little effect on the assembly of tau tangles. Dobutamine, which is used for the rapid treatment of heart attacks and heart failure, was found to have some benefit. However, because its effects are very short-lived, and because it needs to be administered intravenously, it is not ideal as a basis for treatment of Alzheimer's disease.

Further tests using a range of analytical techniques all revealed salbutamol could inhibit tau aggregation in vitro. Tests where salbutamol was added to solutions containing tau resulted in drastically reduced density of fibrous tau structures responsible for the tau neurofibrillary tangles.

The researchers believe that salbutamol interacts with an early stage of tau fibril formation, reducing their ability to form an initial nucleus which drives the aggregation process.

Because it is easily ingested, absorbed into the brain, and remains in the body for several hours, salbutamol has attractive properties as a research avenue for potential new treatment for Alzheimer's.

Dr. David Townsend, of Lancaster University and lead author of the research, said: "Our work highlights the potential impact of repurposing drugs for secondary medical uses, by discovering a novel therapeutic strategy that impedes the molecular pathology of Alzheimer's disease, and which may have otherwise gone unstudied.

"Salbutamol has already undergone extensive human safety reviews, and if follow up research reveals an ability to impede Alzheimer's disease progression in cellular and animal models, this drug could offer a step forward, whilst drastically reducing the cost and time associated with typical drug development."

Professor David Middleton, co-author of the research, said: "This work is in the very early stages and we are some way from knowing whether or not salbutamol will be effective at treating Alzheimer's disease in human patients. However, our results justify further testing of salbutamol, and similar drugs, in animal models of the disease and eventually, if successful, in clinical trials."

Dr. Rohanah Hussain, of Diamond Light Source, Senior Beamline Scientist and co-author said: "Diamond B23 beamline unique micro-collimated beam has made high throughput CD possible allowing the screening of many compounds through structural activity correlation crucial in drug discovery."

The researchers say that current asthma inhalers result in only a small amount of salbutamol reaching the brain and so, if further research is successful, a new delivery method would also need to be developed. They add that future research could also focus on other asthma drugs that are chemically similar to salbutamol, but which circulate in the bloodstream for much longer.

To read more, click here

Asthma puffer med Salbutamol cuts Parkinson’s risk by half

Ok, answers about the previous parkinsons worthless article are here.
https://scienceblog.com/496061/asthma-puffer-med-clenbuterol-cuts-parkinsons-risk-half/
Norwegian researchers have found that using a common asthma medicine cuts in half the likelihood of developing Parkinson’s disease.

The scientists examined data from more than 100 million prescriptions and studied the effects of 1,126 different medicines over that last 11 years in Norway. They were looking to see which compounds might impact levels of the α-synuclein gene in neuroblastoma cells. α-synuclein is a protein that collects in the brains of people with Parkinson’s and forms clumps thoughts to impact motor function.
The drug screening turned up four molecules that had an impact. Three of these were asthma medicines that  target the β2-adrenoreceptor (β2AR). And one of these lowered levels of the of the α-synuclein gene in the Parkinson’s impacted parts of the brain.
“Our analysis of data from the whole Norwegian population has been decisive for the conclusion in this study,” says Professor Trond Riise, who leads the study. The Norwegian research came after Harvard scientists had earlier found similar effects in animal tests and in lab experiments on brain cells.
“We analysed the whole Norwegian population and found the same results as in the animal testing at Harvard University,” Riise said. “These medicines have never been studied in relation to Parkinson’s disease.”
Riise and team looked at medical records of more than 4 million people in Norway between 2004 and 2014and discovered those taking salbutamol (also known as albuterol) had a far lower likelihood of developing Parkinson’s. Conversely, they found people on propranolol, a drug for treating high blood pressure that turns off β2AR, had double the risk.
The insights could prove a boon to Parkinson’s researchers and clinicians as despite its prevalence, few good treatments (let alone a cure) exist for the debilitating condition. “Our discoveries may be the start of a totally new possible treatment for this serious disease,” Riise said. “We expect that clinical studies will follow these discoveries.”

Asthma drug may thwart Parkinson’s disease - Salbutamol

You might very well need this so you better hope that this is followed up better than any stroke research is.

Parkinson’s Disease May Have Link to Stroke

Or are the stem cells better?

Injecting stem cells into the brain reverses Parkinson’s symptoms in monkeys

The newest here:

Asthma drug may thwart Parkinson’s disease - Salbutamol 

By Mitch LeslieAug. 31, 2017 , 2:00 PM

When people with asthma have trouble breathing, they may reach for an inhaler containing salbutamol, a drug that expands the airways. Salbutamol may have another beneficial effect—protecting against Parkinson’s disease. Individuals who inhaled the highest doses of salbutamol were about half as likely to develop the devastating neurological condition as those who didn’t take the drug, a study reveals.
“I’m sure it’s going to be a landmark paper,” says neurologist Joseph Jankovic of Baylor College of Medicine in Houston, Texas, who wasn’t involved in the research.
In Parkinson’s disease, gobs of the protein α-synuclein accumulate in certain brain cells and may kill them. Scientists have tried to craft drugs that speed the elimination of the protein or prevent it from clumping. Neurologist and genomicist Clemens Scherzer of Harvard Medical School in Boston and colleagues decided to try a different strategy. “We wanted to find a drug that could turn down the production of α-synuclein,” he says.

To identify promising compounds, the team grew human nerve cells in the lab and tested whether more than 1100 medications, vitamins, dietary supplements, and other molecules altered their output of α-synuclein. Three of the drugs that cut the protein’s production, including salbutamol, work by stimulating the b2-adrenoreceptor—a molecule on some body cells that triggers a variety of effects, including relaxing the airways. The researchers found that these drugs appear to alter how tightly the DNA containing the α-synuclein gene coils, and thus whether the gene is active.
Salbutamol is one of the world’s most frequently used drugs, and the researchers wondered whether people who took it were less likely to have Parkinson’s disease. “You need to have very large prescription databases with many years of follow-up to do this analysis,” Scherzer says. The researchers found such a database in Norway, which keeps records of all drugs prescribed for each of its 4.6 million residents. The disease was rare. Roughly 0.1% of people who didn’t use the drug developed Parkinson’s disease. The rate among people who used salbutamol was less than 0.04%. After the researchers corrected for factors such as age and education, they determined that Norwegians who had taken salbutamol at least once in their lives were about one-third less likely to develop Parkinson’s disease.
How much protection salbutamol provided depended on the dosage. Compared with Norwegians who didn’t use the drug, people who took the highest doses between 2004 and 2007 were about half as likely to get the disease in the subsequent 7 years. In contrast, patients who took the lowest doses had only slightly lower odds of developing Parkinson’s disease in that period, the researchers report online today in Science.
The results are “fascinating” and “come out of the blue,” says neurologist Anthony Lang of the University of Toronto in Canada. However, he has misgivings about the analysis of the Norwegian data because salbutamol’s influence on α-synuclein appears to be so powerful that it’s surprising we ever see a Parkinson’s patient with asthma, he says. Given that some people do have both diseases, other factors that correlate with salbutamol use might be affecting Parkinson’s disease susceptibility. “We have to take other possible explanations into account,” he says.
Researchers aren’t sure about the best way to harness the results to benefit patients. Clinical trials of salbutamol or related drugs are one possibility. However, none of these drugs is optimized to enter the brain, says neuroscientist Andrew West of the University of Alabama in Birmingham. “The drugs that are going to be ideal for targeting [α-synuclein] have yet to be developed.”
Scherzer says that any clinical trials are “a few years off.” He notes that 16 recent trials of potential Parkinson’s disease treatments have failed. He and his colleagues don’t want to have No. 17.

Posted in:

• Health

doi:10.1126/science.aap8401