Evolution may have been our planet's first recycler. When organisms evolved useful proteins, they tend to get re-used in unrelated processes. So, a single family of proteins may regulate the development of everything from the brain to the blood to the bones.

This is one reason that drugs often have off-target effects. While the drug was designed to latch on to a specific protein in one tissue, that protein or a close relative may be doing something important in a different tissue. While that's generally viewed as a problem, it can also be helpful. Researchers are finding that some drugs can be effective against diseases for which they were never intended.

That may be the case for an asthma medication called clenbuterol. It and a series of related drugs came through a screen that targeted a very different disorder: Parkinson's disease, caused by the death of specific nerve cells in the brain. And a search through the drug-use history of Norway suggests that the discovery is more than a fluke.

Parkinson's and proteins

Parkinson's disease is caused by the death of a specific group of neurons that help control muscle activity. As these neurons die, people progressively lose control of their voluntary muscles, ultimately leading to uncontrolled tremors. Like Alzheimer's and other neurodegenerative diseases, Parkinson's has been associated with tangles of malformed proteins that accumulate in the dying cells.

In many of these diseases, it's not clear whether these tangles are a cause—the protein problems are killing the cells—or a symptom. It could be possible that once a cell starts dying, it's no longer able to clean up aberrant proteins. In Parkinson's, however, there's some sign that the protein tangles are a cause. Parkinson's tangles are made of a protein called α-synuclein, and people with extra copies of that gene are at increased risk of developing Parkinson's. So, having an excess of the protein that forms the tangle appears to predispose nerve cells to dying.

A large international team of researchers decided that this might be a good way to identify targets for Parkinson's drugs. They took a nerve cell line that normally expresses α-synuclein and tested over 1,000 drugs or potential drugs on it, looking for any that would lower the expression of the the gene. They found 35, one of which is known to activate the receptor for adrenaline (also known as epinephrine).

There are a lot of drugs that target the adrenaline system, so the team tested similar drugs in the same assay. Three of them reduced the activity of α-synuclein (the Parkinson's gene), so this seemed to be a real effect. Better yet, two of them were already known to cross the blood-brain barrier, so could potentially reach the cells that Parkinson's kills.

But something that works in cultured cells will often fail miserably when tested in animals. So the team turned to mice, showing that when they injected the drug into mice it made it to the brain and reduced the activity of α-synuclein. They also obtained animals that were missing the gene that encodes the protein targeted by these drugs. These mice had greatly elevated levels of α-synuclein. And, critically, the drug no longer was able to reduce those levels. So this seems to be a biologically relevant pathway.

A human experiment

Normally, this would be the point where we say that several years' worth of safety testing and clinical trials would be needed to learn more. But remember, the chemicals being tested here are actually drugs. And it's not so much that these specific chemicals are needed; it appears that most chemicals that activates the adrenaline receptor should also work to reduce α-synuclein levels. And, conveniently, these are commonly used to treat asthma, since adrenaline helps relax the muscles on our airways.

Even more conveniently, the Norwegian health system has been tracking every prescription handed out in the country since 2004, linking them to the patient records in the country's national health system. So the researchers looked at Parkinson's incidence in everyone who had received the drug salbutamol, which was one of the three that had come out of their screen.

People who received the drug were diagnosed with Parkinson's at two-thirds the rate of people who hadn't. (The 95 percent confidence interval ranged from 0.58 to 0.76, all values that indicate a reduced risk.)

To provide even more evidence, the team looked at a drug called propranolol. This is a beta blocker, typically used to calm irregular heartbeats and high blood pressure specifically because it blocks the activation of the adrenaline receptor. People taking this drug were at over double the risk of being diagnosed with Parkinson's. Even the low end of the 95 percent confidence interval put the risk at over 1.5 times, and the high end was at triple the risk.

As a final piece of evidence, the authors obtained cells from an individual that carries an extra copy of the α-synuclein gene, which predisposes them to Parkinson's. These cells were converted to stem cells, and the stem cells converted to neurons. Treating them with one of the drugs that came through the screen reduced α-synuclein expression, lowered the mortality of the cells, and kept their energy metabolism under better control.

Don't try this at home

On their own, none of these results would be decisive; after all, biology only requires its evidence to have a five percent risk of occurring by chance. But the huge variety of data, obtained in different systems and using very different methods, all points in the same direction here. And the underlying idea—a focus on α-synuclein—is based on some pretty solid biology.

That said, it's still too early to go rushing out to get prescriptions for any of these drugs. They're "not currently FDA-approved for [Parkinson's] treatment," as the authors note. The team goes on to point out that the drugs can exacerbate cardiovascular disease. The flipside of that latter point is that the drugs that enhance the risk of Parkinson's are used to treat cardiovascular disease, specifically high blood pressure and heart arrhythmias. And both of those can definitely kill you.

So, while the focus on existing drugs may help in terms of limiting the amount of basic characterization and safety testing that needs to be done, it doesn't mean the decision whether or not to use the drugs will be a simple one.

Science, 2017. DOI: 10.1126/science.aaf3934 (About DOIs).