Could Repurposed Asthma Drugs Treat Parkinson’s Disease?
Posted on by Dr. Francis Collins
I had asthma as a child, and I still occasionally develop mild wheezing from exercising in cold air or catching a bad cold. I keep an inhaler on hand for those occasions, as this is a quick and effective way to deliver a medication that opens up those constricted airways. Now, an NIH-supported team has made the surprising discovery that some asthma medicines may also hold the potential to treat or help prevent Parkinson’s disease, a chronic, progressive movement disorder that affects at least a half-million Americans.
The results, published recently in the journal Science, provide yet another example of the tremendous potential of testing drugs originally intended for treating one disease for possible use in others . In this particular instance, researchers screened a library of more than 1,100 well-characterized chemical compounds—including drugs approved by the Food and Drug Administration for treating asthma—to see if they showed any activity against a molecular mechanism known to be involved in Parkinson’s disease.
It’s long been known that the brains of people with Parkinson’s disease become clogged with abnormal clumps of protein in an area essential for controlling movement. Twenty years ago, scientists discovered that those clumps, known as Lewy bodies, are composed primarily of defective or excess amounts of a protein called alpha-synuclein (a-syn). The discovery raised the tantalizing possibility that treatments designed to prevent or clear those abnormal clumps could be found. And yet decades later, the difficult search continues.
Now a team led by Clemens Scherzer at Harvard Medical School and Brigham & Women’s Hospital, Boston, has reached the remarkable conclusion that FDA-approved drugs capable of lowering a-syn in the brain might already exist. Instead of focusing on compounds that target the protein itself, the researchers sought ones that could reduce the activity of the SNCA gene, which encodes a-syn. The hope was that, rather than cleaning up a-syn proteins after the fact, there might be a way to tamp down their production at the source.
After testing a wide array of compounds, the researchers identified four that significantly reduced activity of the SNCA gene in human cells in the lab. Interestingly, three of the four worked by activating precisely the same cell surface protein: the beta2-adrenoreceptor, which when acted on by natural molecules like adrenalin is capable of relaxing smooth muscle cells in the airways. In fact, the three drugs—salbutamol, clenbuterol, and metaproterenol—all bind to the beta2-adrenoreceptor and are frequently used for the treatment of asthma and other breathing problems.
To learn more, the researchers tried treating human neuronal cells in the lab. Those studies confirmed that all three drugs lowered the activity of the SNCA gene. Importantly, the reduced gene activity also reduced levels of a-syn protein.
In people with Parkinson’s disease, neurons in a portion of the brain called the substantia nigra are hardest hit. So, the researchers examined that portion of the brain in mice. After 24 hours of treatment with clenbuterol, levels of a-syn in that key portion of the mouse brain were reduced, indicating scientists definitely were onto something. Treatment in a mouse model of Parkinson’s disease was also protective, and further studies with clenbuterol confirmed these results in brain cells derived from a person with Parkinson’s disease.
The treatment seemed to be working in mice and human neurons in cell culture. But would it also work in people? To get a sneak peek at the answer, the researchers did something quite novel. They tapped into the Norwegian Prescription Database, working with Trond Riise at the University of Bergen, Norway.
Since 2004, Riise and his colleagues have been collecting medical records and drug prescription data for 4.6 million Norwegians. Remarkably, the researchers uncovered evidence that people who had taken salbutamol were indeed less likely to develop Parkinson’s disease.
On the other hand, Norwegians who had taken a beta-blocking drug called propranolol for their heart disease showed just the opposite: an increased risk of Parkinson’s disease. Why would that be? It turns out that both drugs act on the beta2-adrenoreceptor, but in opposite ways. Salbutamol activates the receptor, and thus reduces activity of the SNCA gene. Propranolol instead blocks the receptor’s activity, with a resulting increase of SNCA activity and a-syn production.
As promising as these new findings are, Parkinson’s disease patients and those concerned about their risk for the disease shouldn’t begin taking asthma medications just yet. Rigorous clinical trials designed to test the potential effectiveness of this treatment strategy for Parkinson’s disease are needed first. Still, it just might be that a long-awaited treatment to reduce a-syn levels in the brain might be (quite literally) right under our noses.
 β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease. Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. Science. 2017 Sep 1;357(6354):891-898.
Parkinson’s Disease Information (National Institute of Neurological Disorders and Stroke/NIH)
Clemens Scherzer Lab (Brigham & Women’s Hospital, Harvard Medical School, Boston, MA)
NIH Support: National Institute of Neurological Disorders and Stroke
- Click to share on Pinterest (Opens in new window)
- Click to share on Tumblr (Opens in new window)
- Click to share on Reddit (Opens in new window)
- Click to share on Telegram (Opens in new window)
- Click to share on WhatsApp (Opens in new window)
- Click to share on Skype (Opens in new window)
- Click to print (Opens in new window)
Tags: a-syn, alpha-synuclein, approved drugs, asthma, beta blocker, beta2-adrenoreceptor, brain, clenbuterol, drug repurposing, drugs, genomics, inhaler, metaproterenol, motor system disorder, neurology, Norwegian Prescription Database, Parkinson's disease, Propranolol, repurposing drugs, salbutamol, SNCA gene