Date: January 2019
Prepared by SIC member: Connie Marras, MD
Authors: Lorraine V. Kalia, MD, PhD, FRCPC; Raymond Y. Lo, MD, PhD
Editor: Stella Papa, MD
In 2017, a study by Scherzer and colleagues suggested that β2-adrenoreceptor agonists had the ability to reduce alpha-synuclein levels and to protect against MPTP toxicity. These findings were accompanied by epidemiological data that found an inverse relationship between β2-adrenoreceptor agonists and PD risk. Furthermore, other epidemiological studies and basic science data suggested that beta antagonists may have the opposite effects. However, a number of successive studies assessing these classes of agents reported variable results. We asked Dr. Lorraine Kalia, a movement disorder neurologist and basic scientist, and Raymond Lo, a movement disorder neurologist and epidemiologist, to discuss these studies and their clinical implications from two different perspectives.
Synopsis of the Basic Science Data
The focus on β2-adrenoreceptor agonists as potential disease-modifying agents in PD began with an interesting study by Scherzer and colleagues. They tested the hypothesis that chemical compounds able to reduce alpha-synuclein levels have the potential to be disease-modifying therapies for PD. To begin to test this hypothesis, they screened a library of >1000 compounds and made the novel discovery that β2-adrenoreceptor agonists – specifically metaproterenol, clenbuterol and salbutamol – can reduce endogenous alpha-synuclein mRNA and protein levels in a human cell line. Furthermore, they demonstrated that β2-adrenoreceptor agonist treatment reduced alpha-synuclein mRNA and protein levels in iPSC-derived neuronal precursor cells from PD subjects with SNCA locus triplication, in cultured rat primary cortical neurons, and in substantia nigra of wild-type mice. An epigenetic mechanism may be the means by which stimulation of β2-adrenoreceptors regulates alpha-synuclein expression since repression of SNCA transcription was associated with a reduction in histone 3 lysine 27 acetylation (H3K27ac). Scherzer and colleagues tested the disease-modifying potential of clenbuterol in a mouse MPTP model, and these initial preclinical studies demonstrated that combined pre- and post-MPTP clenbuterol treatment prevented loss of dopaminergic neurons in the substantia nigra, presumably due to reduced alpha-synuclein levels. These data present a compelling case for investigating this class of agents in Parkinson’s disease but several important questions need to be answered first. These include whether or not β2-adrenoreceptor agonists can prevent dopaminergic neuron loss in different models of dopaminergic cell loss that may present various levels of stability, and once the neurodegenerative process has already been initiated. Thus, it could be useful to test the effect of clenbuterol treatment post-MPTP lesion.. It is also uncertain whether or not the effect of clenbuterol on alpha-synuclein levels and dopaminergic neuron loss are related to its action on β2-adrenoreceptors or due to off-target effects. Therefore, a significant amount of work is yet necessary to draw conclusions on the neuroprotective actions of β2-adrenoreceptor agonists.
Is it Safe to Use Beta Blockers in PD Patients? A Basic Science Perspective
Scherzer and colleagues present more limited data on the effects of β2-adrenoreceptor antagonism with propranolol. They do demonstrate that propranolol can increase H3K27ac and alpha-synuclein levels in cultured cells. However, they do not test the effects of propranolol on alpha-synuclein levels and MPTP toxicity (or other measures of neurodegeneration) in any animal model. Thus, their lab work does not provide any evidence that propranolol is toxic to neurons, and I am not aware of any previous cell or animal studies that have suggested propranolol can cause or exacerbate neurodegeneration.
The strength of the epidemiological evidence that β2-adrenoreceptor agonists are protective against PD
Based on the β2-adrenoreceptor modulation hypothesis, two epidemiological studies from Norway1 and Israel2 showed that the use of the β2-agonist salbutamol is associated with a reduced risk of PD. Both studies used different proxies (comorbid chronic pulmonary obstructive disease or socioeconomic status) to control for smoking because smoking is known to be a strong inverse risk factor for PD. Lag-time and dose-response were also taken into consideration in study design. Positive findings were consistent in these two studies. Furthermore, with the additional analysis of other β2-agonists in the Israeli study, data suggest that the inverse association between the use of β agonists and PD is robust. However, the potential for residual confounding factors even after controlling for smoking proxies remains significant. A more recent study from the US3 used a validated smoking variable derived from International Classification of Disease (ICD) codes and other demographic information for confounding adjustment and found the inverse association to be significantly nullified. From a clinician’s perspective, β agonists are bronchodilators and almost always applied in respiratory distress, which may or may not be related to smoking. In other words, the confounding association of smoking with β agonist indication seems by and large inevitable, and thus we are still far from concluding that β agonists are protective against PD. Nevertheless, this hypothesis provides a new insight into the pathophysiology of PD, and we do anticipate new agents targeting α-synuclein gene via β-adrenoreceptors for PD prevention or treatment.
1. Mittal S. et al. Science. 2017 Sep 1;357(6354):891-898.
2. Gronich N. et al. Mov Disord. 2018 Sep;33(9):1465-1471
3. Searles Nielsen S. et al. Ann Neurol. 2018 Nov;84(5):683-693.
The strength of the evidence that β2-adrenoreceptor antagonists are harmful
The two studies from Norway and Israel also found that β-adrenoreceptor antagonists, particularly propranolol, were associated with increased risks of PD. Propranolol is known to be often prescribed for controlling tremor, and thus the positive association between propranolol and PD may well come from the common association of tremor preceding PD diagnosis, and here again there is confounding by indication. Searles Nielsen et al.3 found that a significant relationship between propranolol and PD in the US Medicare Beneficiary database disappeared soon after controlling for tremor. Moreover, they showed that when β-antagonists are not indicated for tremor, they even seem to reduce the risk of PD.
Overall, the evidence that β antagonists are harmful is still insufficient. In addition, we should also pay attention to the clinical significance of the data. The number of propranolol users developing PD in the Norway study was only 41 out of 65598 person-years during a follow-up period of 11-years. This shows that even if the non-selective β antagonist is harmful, the clinical effect would be minimal.
Clinical implications - Is there any place for avoiding beta antagonists in individuals with PD at this time?
I think at this point there is no place for avoiding β-antagonists in individuals with PD. The modulating effect of β-adrenoreceptors on α-synuclein gene expression is an interesting hypothesis; however, the use of β- antagonists for tremor results in major challenges interpreting observational studies. Even if a negative (deleterious) effect were convincingly demonstrated, before making changes to treatment the benefits of these agents for their established indication (tremor) would need to be considered in clinical decision-making at the individual level.
Summary for clinical care in PD
These two summaries of the relationship between beta adrenoceptor modulating drugs and PD from very different perspectives both highlight the questions that remain to be answered before we alter our clinical practice. Both agonists and antagonists are readily available and are very commonly used drugs. It is inevitable that we will face questions from our PD patients about the promise and the safety of these agents. The discussions above call for caution in drawing premature conclusions and suggest that clinical decisions should be based on the well-established indications for these drugs. The findings of these studies are fascinating, and more studies are needed from both basic science and clinical research to understand the effects of these drugs on PD and their underlying mechanisms.