Salbutamol, a β2-adrenoreceptor (β2AR) commonly used to treat asthma, cuts the risk for Parkinson's disease (PD) by about a third, new research suggests.

On the other hand, propranolol, a β-blocker prescribed for hypertension, is linked to a doubling of the risk for PD, the same study shows.

These results could signal a radically new treatment approach for PD, study author Clemens R. Scherzer, MD, Neurogenomics Laboratory and Parkinson Personalized Medicine Program, and Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"This is an exciting first step for a potential new treatment avenue for Parkinson's disease."

However, Dr Scherzer cautioned that much work still needs to be done to replicate the results, optimize the drug's effect on the brain, and complete clinical trials.

The study was published in the September issue of Science.

Norwegian Collaboration

The brain of most patients with PD is riddled with intracellular accumulations of α-synuclein protein known as Lewy bodies. Clearance of this protein, along with blockade of its transformation into toxic species, or amelioration of its downstream consequences, has traditionally been the focus of drug development in PD.

Researchers hypothesized that chemical compounds designed to reduce the transcription of the α-synuclein gene (SNCA) could prevent or slow the disease process in selected patients. But that idea lacked a "druggable" target.

For the new study, Dr Scherzer and his colleagues took a "drug repurposing" approach. They carried out a screen of 1126 compounds, including drugs approved by the US Food and Drug Administration (FDA), as well as natural products and health supplements, to find agents that lower synuclein expression in neurons.

From that screen came four "hits" — three of them agonists of β2AR — salbutamol, clenbuterol, and metaproterenol.

The researchers discovered that the β2AR is a regulator of SNCA. β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Given that β2AR modulates SNCA expression, researchers hypothesized that use of β2AR ligands would affect PD risk.

Dr Scherzer and colleagues collaborated with Trond Riise, PhD, University of Bergen in Norway, who was instrumental in analyzing nationwide databases that provide information on PD rates and on asthma drug use throughout Norway.

The researchers focused on salbutamol because it's the most commonly used β2AR agonist in Norway and crosses the blood–brain barrier (BBB), particularly at high doses. Clenbuterol is not approved for human use in the United States, and metaproterenol, while FDA approved, is not known to cross the BBB.

The investigators broke salbutamol use into "ever used" and "never used." The "ever used" category could include patients taking the drug only a few times.

As well as salbutamol, the researchers looked at propranolol, the most commonly used β2AR antagonist. The analyses of neuronal cells and primary neurons had found that if β2AR was knocked out, or chemically blocked, there was a dramatic — over a 100% — increase in levels of synuclein expression.

Dose-Dependent Effect

"There is good reason to think that too much α-synuclein leads to Parkinson's disease," said Dr Scherzer.

The study population included all individuals living in Norway on January 1, 2004, a total of 4.6 million people.

Researchers carried out two separate Cox proportional hazard models, adjusting for sex, age, and level of education. Over 11 years of follow-up, salbutamol was associated with decreased risk for PD, with a rate ratio of 0.66 (95% confidence interval [CI], 0.58 - 0.76).

"Norwegians who took salbutamol during the follow-up period had significantly reduced risk for PD. Overall, it was 34% reduction," said Dr Scherzer.

There was a dose effect, he added. "Those taking the highest doses of salbutamol had the strongest effect, while those taking medium doses had a medium effect and those taking low amounts essentially had no effect."

To investigate whether other asthma drugs had the same effect, researchers looked at corticosteroids, a completely different class of asthma medication. "We found no effect on PD risk; it was reassuring that it's specific to salbutamol," said Dr Scherzer.

The researchers did not have direct evidence on smoking habits, which may be a confounding factor in the association between asthma drugs and PD. Tobacco exposure is associated with early childhood asthma, and smoking has been associated with decreased risk for PD.

However, they did adjust for education level, which, in Norway, is a reasonable proxy for smoking. This analysis showed only a slight change in the effect of salbutamol.

"So it's unlikely that smoking can fully explain the association between salbutamol and PD," said Dr Scherzer.

Increased PD Risk

Looking at propranolol, the researchers found that this drug was associated with a markedly increased risk for PD, with a rate ratio of 2.20 (95% CI, 1.62 - 3.00).

In addition to treating cardiovascular indications, particularly hypertension, propranolol is used for essential tremor, a neurologic condition that might mimic a first sign of PD. After excluding patients taking the drug for a neurologic indication, the study found little change in the association.

Introducing time lags of 1 and 2 years between first exposure to propranolol and PD onset only slightly reduced the effect estimates. This suggests that it's unlikely that reverse causality explains most of the association between propranolol and PD.

One of the next steps is to determine whether the association between salbutamol and PD risk extends beyond Norway. "We need to look at whether we see the same association in other, more heterogeneous populations," said Dr Scherzer.

He also sees room to "optimize" the efficacy of β2AR drugs. This, he said, can be done "by making the drugs more brain-penetrant, more effective for lowering α synuclein expression, and longer acting, and by reducing cardiovascular side effects."

Taking this drug-repurposing approach speeds up the process by which medicines are used clinically. "A lot is known already about these medications, particularly their safety profile, so that could make translation to the clinic faster, and time to patients shorter," said Dr Scherzer.

The authors note this association does not imply causation and that β2AR agonists are not currently FDA approved for PD treatment. Dr Scherzer also points out that cardiovascular disease can be exacerbated by β2AR agonists.

"Exciting" Research

Commenting on the findings for Medscape Medical News, Honglei Chen, MD, PhD, Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, and Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, to comment on the study. Dr Chen's research focuses on PD.

"This is an exciting study with a systematic approach to screening for drugs or chemicals that may be used for treating PD," said Dr Chen.

"The converging evidence from epidemiological analysis, animal experiment, and stem cell model makes their study conclusion very appealing."

Dr Chen said he "would love" to see further epidemiologic studies to replicate the results that perhaps could better control for potential confounders and exploration of dosage and temporal relationships.

However, Dr Chen added that "the question remains" whether β2AR agonists would be effective once PD is clinically diagnosed.

Dr Scherzer is named as inventor on a patent application held by Brigham & Women's Hospital that relates to modification and combinations of β-adrenoreceptor agonists as potential therapeutics for PD. Dr Chen has disclosed no relevant financial relationships.

Science. 2017;357:891-898. Full text

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