β-adrenoreceptors and the risk of Parkinson's disease

doi:10.1016/S1474-4422(19)30400-4

The Lancet Neurology

Volume 19, Issue 3, March 2020, Pages 247-254

https://doi.org/10.1016/S1474-4422(19)30400-4 Get rights and content

Summary

Background

β-adrenoceptors are widely expressed in different human organs, mediate important body functions and are targeted by medications for various diseases (such as coronary heart disease and heart attack) and many β-adrenoceptor acting drugs are listed on the WHO Model List of Essential Medicines. According to current treatment guidelines, more than a billion patients with neurological disorders have an indication for the use of β-adrenoceptor antagonists (mainly migraine and essential tremor).

Recent developments

An observational study reported a link between the chronic use of the β-adrenoceptor antagonist propranolol and an increased risk of Parkinson's disease, while the chronic use of the β-adrenoceptor agonists was associated with a decreased risk. Further support of this association was provided by a dose-dependent decrease in the risk of Parkinson's disease with chronic β-adrenoceptor agonist (eg, salbutamol) use, and by functional data indicating a possible underlying molecular mechanism. Five additional epidemiological studies have examined the modulation of the risk of Parkinson's disease as a result of the use of β-adrenoceptor-acting drugs in different populations. Overall, similar estimates but different interpretations of the associations were provided. Several findings suggest that the increase in risk of Parkinson's disease associated with β-adrenoceptor antagonists use can be explained by reverse causation because prodromal Parkinson's disease is often associated with non-specific action tremor, which is usually treated with propranolol. The lower risk of Parkinson's disease seen in patients receiving β-adrenoceptor agonists is likely to be indirectly mediated by smoking because smoking has a strong inverse association with Parkinson's disease (people that smoke have a reduced risk of developing Parkinson's disease). Smoking also causes chronic obstructive pulmonary disease, which is treated with β-adrenoceptor-agonist medications. Even if causal, the effect of β-adrenoceptor antagonists on the risk of Parkinson's disease would be small compared with other Parkinson's disease risk factors and would be similar to the risk evoked by pesticide exposure. The estimated risk of Parkinson's disease because of β-adrenoceptor antagonists use corresponds to one case in 10 000 patients after 5 years of propranolol use, and would be considered a very rare adverse effect. Thus, not using β-adrenoceptor antagonists would severely harm patients with recommended indications, such as heart disease or migraine. Similarly, 50 000 people would have to be treated for 5 years with salbutamol to prevent Parkinson's disease in one patient, suggesting that primary preventive therapy studies on disease modification are not warranted.

Where next?

Epidemiological evidence for a causal relationship between use of β2-adrenoceptor antagonists and the increased risk of Parkinson's disease is weak, with other explanations for the association being more probable. Future observational studies are warranted to clarify this association. However, given the very low risk associated with propranolol, most clinicians are unlikely to change their treatment approach.

Introduction

Parkinson's disease is the fastest growing neurodegenerative disease, with a worldwide increase in the number of patients with the disease from 2·5 million in 1990 to 6·1 million in 2016.¹ An ageing society is the main reason for this substantial increase, but declining smoking rates, increasing industrialisation, and additional unknown factors could also contribute.² The prevention of Parkinson's disease has long been recognised as the best strategy to fight this development.3, 4 The International Parkinson and Movement Disorder Society developed a proposal to assess Parkinson's disease risk⁵ based on the age-specific likelihood for Parkinson's disease calculated using a Bayesian classification algorithm including specific risk or protective factors. Since then, the risk factors for Parkinson's disease have been regularly updated to improve the precision of this proposed tool.6, 7

Of the factors that could modulate the risk of Parkinson's disease, β-adrenoceptors have become a possible target.8, 9, 10, 11, 12, 13, 14, 15 Because β-acting agents have a major role in global health care, in this Rapid Review we summarise the observational studies examining the effect of β-adrenoceptors on Parkinson's disease risk and discuss how these new findings might affect the clinical use of these drugs.

Section snippets

Proposed regulation of α-synuclein expression by β2-adrenoceptor agonists and antagonists

α-Synuclein is the main constituent of Lewy bodies,¹⁶ the pathological hallmark of Parkinson's disease in the brain.¹⁷ With increasing disease severity, Lewy bodies and pathological α-synuclein production increase in the brain, from the vagal nucleus to the cortex, in a consistent pattern leading to the Braak pathological staging of Parkinson's disease.¹⁸ Therefore, much research focuses on α-synuclein metabolism, in particular on drugs affecting α-synuclein concentrations. A human cell model

Biological function of the β-adrenoceptors

β-adrenoceptors are a family of G-protein-coupled receptors. β1-adrenoceptors are mainly expressed in cardiac tissue and the CNS, β2-adrenoceptors are expressed in bronchial and blood vessel smooth muscle cells, and β3-adrenoceptors are expressed mainly in the bladder and in adipose tissue, where they primarily regulate relaxation of the bladder and lipolysis. In the heart, blockage of β1-adrenoceptors (eg, by use of β1-selective or non-selective β-adrenoceptor antagonists) decreases heart rate

Epidemiological evidence of risk modulation with β-adrenoceptor acting drugs

Several observational studies have addressed the potential relationships between commonly used drugs (eg, ibuprofen) and Parkinson's disease risk, investigating a hypothetical neuroprotective drug effect.3, 14, 41, 42, 43 However, the results of these studies are contradictory.

Six studies10, 11, 12, 13, 14, 15 have evaluated the risk-modulating effect of β2-adrenoreceptor-acting drugs (figure 1A). β-adrenoceptor antagonists (eg, propranolol) were associated with an increased risk of Parkinson's

Conclusions and future directions

To date, the epidemiological evidence for an increased risk of developing Parkinson's disease because of β-adrenoceptor antagonists is weak, and, from our point of view, alternative explanations are more convincing.12, 14, 15 Under the questionable assumption that the association between Parkinson's disease and β-adrenoceptor antagonists represents a causal relationship, the potential risk by β-adrenoceptor antagonists is similar to the risk evoked by pesticide exposure⁴³ and the strongest

Search strategy and selection criteria

Articles for this Rapid Review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles published between Jan 1, 2017, and Aug 1, 2019, using the search terms “Parkinson's disease and Beta adrenoreceptor”, “Parkinson's disease and β2-adrenoreceptor”, “Parkinson's disease and Beta Blocker”, “Parkinson's disease and β2-adrenoreceptor antagonist”, and “Parkinson's disease and β2-adrenoreceptor agonist”. The final reference list was generated on the

References (65)

A Ascherio et al.
The epidemiology of Parkinson's disease: risk factors and prevention
Lancet Neurol
(2016)
TG Ton et al.
Calcium channel blockers and beta-blockers in relation to Parkinson's disease
Parkinsonism Relat Disord
(2007)
T Konno et al.
Autosomal dominant Parkinson's disease caused by SNCA duplications
Parkinsonism Relat Disord
(2016)
L Hertz et al.
Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and [Ca(2+)]i
Neurochem Int
(2010)
G Deuschl et al.
Treatment of patients with essential tremor
Lancet Neurol
(2011)
KF Rabe et al.
Chronic obstructive pulmonary disease
Lancet
(2017)
DW Dodick
Migraine
Lancet
(2018)
GA Roth et al.
Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015
J Am Coll Cardiol
(2017)
M Metra et al.
Heart failure
Lancet
(2017)
M Klapholz
Beta-blocker use for the stages of heart failure
Mayo Clin Proc
(2009)

V Bellou et al.

Environmental risk factors and Parkinson's disease: an umbrella review of meta-analyses

Parkinsonism Relat Disord

(2016)

A Schrag et al.

Prediagnostic presentations of Parkinson's disease in primary care: a case-control study

Lancet Neurol

(2015)

ED Louis et al.

Essential tremor seems to be a risk factor for Parkinson's disease

Parkinsonism Relat Disord

(2016)

Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Lancet Neurol

(2018)

ER Dorsey et al.

The emerging evidence of the Parkinson pandemic

J Parkinsons Dis

(2018)

C Marras et al.

Environment, lifestyle, and Parkinson's disease: implications for prevention in the next decade

Mov Disord

(2019)

D Berg et al.

MDS research criteria for prodromal Parkinson's disease

Mov Disord

(2015)

RB Postuma et al.

Advances in markers of prodromal Parkinson disease

Nat Rev Neurol

(2016)

AJ Noyce et al.

Meta-analysis of early nonmotor features and risk factors for Parkinson disease

Ann Neurol

(2012)

L Magistrelli et al.

Beta2-adrenoceptor agonists in parkinson's disease and other synucleinopathies

J Neuroimmune Pharmacol

(2019)

D Savitt et al.

targeting α-synuclein in Parkinson's disease: progress towards the development of disease-modifying therapeutics

Drugs

(2019)

S Mittal et al.

β2-adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease

Science

(2017)

N Gronich et al.

β2-adrenoceptor agonists and antagonists and risk of Parkinson's disease

Mov Disord

(2018)

F Hopfner et al.

Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease

Neurology

(2019)

G Koren et al.

Chronic use of β-blockers and the risk of parkinson's disease

Clin Drug Investig

(2019)

S Searles Nielsen et al.

β2-adrenoreceptor medications and risk of Parkinson disease

Ann Neurol

(2018)

MG Spillantini et al.

Alpha-synuclein in Lewy bodies

Nature

(1997)

FH Lewy

Zur pathologischen Anatomie der Paralysis Agitans

Dtsch Z Nervenheilkd

(1913)

H Braak et al.

Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered

Mov Disord

(2006)

S Mu et al.

Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension

Nat Med

(2011)

PJ Scarpace et al.

Alpha- and beta-adrenergic receptor function in the brain during senescence

Neurobiol Aging

(1988)

AL Gorman et al.

Beta-adrenergic receptors are involved in stress-related behavioral changes

Pharmacol Biochem Behav

(1993)

Cited by (49)

Aporphines: A privileged scaffold in CNS drug discovery
2023, European Journal of Medicinal Chemistry
Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D_1/2/5, serotonin 5-HT_1A/2A/2C and 5-HT₇, adrenergic α/β receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.
Targeting G Protein-Coupled Receptors in the Treatment of Parkinson's Disease
2023, Journal of Molecular Biology
Citation Excerpt :
Moreover, observational data indicated that patients treated with β2A-R antagonists had an increased risk of developing PD, while patients treated with β2A-R agonists were protected from PD.201 However, follow-up studies have suggested that these associations may have been driven by confounding factors.202–203 Specifically, the β2A-R antagonist propranolol is often prescribed for the treatment of tremor, a symptom which can occur in the prodromal stages of PD.
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized in part by the deterioration of dopaminergic neurons which leads to motor impairment. Although there is no cure for PD, the motor symptoms can be treated using dopamine replacement therapies including the dopamine precursor L-DOPA, which has been in use since the 1960s. However, neurodegeneration in PD is not limited to dopaminergic neurons, and many patients experience non-motor symptoms including cognitive impairment or neuropsychiatric disturbances, for which there are limited treatment options. Moreover, there are currently no treatments able to alter the progression of neurodegeneration. There are many therapeutic strategies being investigated for PD, including alternatives to L-DOPA for the treatment of motor impairment, symptomatic treatments for non-motor symptoms, and neuroprotective or disease-modifying agents. G protein-coupled receptors (GPCRs), which include the dopamine receptors, are highly druggable cell surface proteins which can regulate numerous intracellular signaling pathways and thereby modulate the function of neuronal circuits affected by PD. This review will describe the treatment strategies being investigated for PD that target GPCRs and their downstream signaling mechanisms. First, we discuss new developments in dopaminergic agents for alleviating PD motor impairment, the role of dopamine receptors in L-DOPA induced dyskinesia, as well as agents targeting non-dopamine GPCRs which could augment or replace traditional dopaminergic treatments. We then discuss GPCRs as prospective treatments for neuropsychiatric and cognitive symptoms in PD. Finally, we discuss the evidence pertaining to ghrelin receptors, β-adrenergic receptors, angiotensin receptors and glucagon-like peptide 1 receptors, which have been proposed as disease modifying targets with potential neuroprotective effects in PD.
Facile synthesis of Pt/polyoxometalate/hollow carbon sphere tri-component nanoparticles via a “double gain strategy” for high-performance electrochemical sensing of adrenaline
2023, Talanta
In this study, we designed and successfully synthesized the Pt/polyoxometalate/hollow carbon sphere (Pt/POM/HCS) tri-component nanoparticles (NPs) by a pollution-free, efficient, and convenient method. HCSs with outstanding chemical stability and conductivity are self-generated by acid etching and calcination of silica spheres synthesized by a hard template method. HCSs have a hollow internal structure that provides specific three-dimensional storage space, and can increase the surface area. The mesoporous system is beneficial to providing numerous mass transfer passageways and immobilizing NPs. In addition, we introduced a “double gain strategy”, by taking advantage of POMs as reducing and bridging agents, to achieve the loading of ultrafine Pt NPs on the surface of HCSs. Pt NPs have excellent stability and unique electrocatalytic activity. As a result of the synergistic effect of HCSs and ultrafine Pt NPs, the electrochemical sensing of adrenaline exhibits high-performance catalytic activity, sensitivity, suitable linearity range (0.16 μM−1.195 mM), and low limit of detection (57.5 nM, S/N = 3), excellent stability, and reproducibility. The developed platform is a sensitive and effective adrenaline electrical sensing platform with broad practical application prospects.
Integrated plasma pharmacochemistry and network pharmacology to explore the mechanism of Gerberae Piloselloidis Herba in treatment of allergic asthma
2022, Journal of Ethnopharmacology
Gerberae Piloselloidis Herba (GPH), a commonly used traditional medicine in China, is derived from Gerbera piloselloides (Linn.) Cass. It is featured by its special bioactivities as antitussive, expectorant, anti-asthma, anti-bacterial, anti-tumor, uterine analgesia, and immunity-enhancing. With a long history of medication in ethnic minority areas in China, it is often used as an effective treatment for cough and sore throat as well as allergic asthma. Although our previous investigation also has discovered GPH performed effective treatment on allergic asthma, its underlying mechanism remains unclear.
This research aims to reveal the pharmacological mechanism of GPH in the treatment for allergic asthma through combination of plasma pharmacology and network pharmacology.
Firstly, the components of GPH in blood samples were identified using UHPLC- Q-Orbitrap HRMS. An interaction network of "compound-target-disease" was constructed based on the compounds confirmed in blood and on their corresponding targets of allergic asthma acquired from disease gene databases, predicting the possible biological targets and potential signal pathways of GPH with the network pharmacology analysis. Then, a molecular docking between the blood ingredients and the core targets was carried out using the Autodock Vina software. Subsequently, after establishing a mouse model with allergic asthma induced by ovalbumin (OVA), the effect of GPH on allergic asthma was evaluated by analyzing a series of indicators including behavior, lung pathological changes, inflammatory factors in serum and bronchoalveolar lavage fluid (BALF). Finally, the key pathway and targets predicted by network pharmacology and molecular docking were further verified using Western blot analysis.
Eleven chemical constituents (such as arbutin, neochlorogenic acid, chlorogenic acid, etc.) were identified through the analysis of plasma samples, on which basis a total of 142 genes intersecting GPH and allergic asthma were collected by network pharmacology. After performing enrichment analysis of these genes in gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG), it was found that arbutin-related targets mainly focused on phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signal pathway, while luteolin and marmesin -related targets tended to locate at Interleukin-17 (IL-17) signal pathway. Meanwhile, the findings of molecular docking suggested that such components as arbutin, luteolin and marmesin entering into blood had good binding with the core targets related to PI3K/Akt and IL-17 pathways. In addition, GPH improved the OVA-induced asthma symptoms, the alveolar septa thickening and the infiltration of inflammatory cell around bronchi and bronchioles as well as reduced the levels of IgE, IL-8 and TNF-α in serum or BALF. Furthermore, GPH could inhibit the phosphorylation level of Akt and the expression of PI3K, an efficacy supported by the findings by way of Western blot which suggests that GPH in the treatment of allergic asthma was linked to PI3K/Akt signal pathway.
In this study, a comprehensive strategy to combine the UPLC-Q-Orbitrap HRMS with network pharmacology was employed to clarify the mechanism of GPH against allergic asthma, a finding where GPH may inhibit PI3K/Akt signal pathway to protect mice from OVA-induced allergic asthma. This study provides a deeper understanding of the pharmacological mechanism of GPH in treatment of asthma, offering a scientific reference for further research and clinical application of GPH in terms of allergic asthma.
Beta-adrenergic drugs and risk of Parkinson's disease: A systematic review and meta-analysis
2022, Ageing Research Reviews
Citation Excerpt :
Consistent with previous studies, we found beta-agonist exposure overall to be negatively associated with the risk of PD (Mittal et al., 2017; Cheng et al., 2015; Gronich et al., 2018; Stacey et al., 2018). Hopfner et al. argued that the decreased risk of PD with beta-agonist exposure is a result of indirect association with nicotine exposure (through smoking), acting as the uncontrolled confounder and cited the lack of a proposed biological mechanism for protection against PD (Hopfner et al., 2020, 2019). However, in further analysis, Hopfner et al. adjusted for the markers of smoking (inhaled corticosteroids, inhaled anticholinergics, and COPD diagnosis) and established the effect, although attenuated, remained significant (aOR: 0.64, 95%CI: 0.42–0.98) (Hopfner et al., 2019).
Parkinson’s Disease (PD) is a neurodegenerative disorder manifested by rest tremor, rigidity, bradykinesia, and postural instability. Recent pharmaco-epidemiological studies evaluating beta-adrenergic drug use and risk of PD have reported conflicting findings.
This systematic review and meta-analyses evaluate the association between beta-adrenergic (agonists and antagonists) drugs’ use and PD.
An electronic literature search of eight databases was performed from inception to July 2021 to identify pharmaco-epidemiological studies (case-control and cohort) reporting the risk of PD in beta-adrenergic users compared to non-users. We used the generic inverse variance method and RevMan (5.3.5) to estimate pooled adjusted risk ratios (aRRs) of PD using a random-effects model.
Of 3168 records, 15 studies (10 case-control; five cohort) with 6508,877 participants, including 87,011 PD cases, were included. In the pooled analysis (n = 10) including any beta-antagonist users, compared with non-users, the aRR for PD was 1.19 (CI: 1.05,1.35); for any beta-agonist users (n = 8) aRR for PD was 0.87 (CI: 0.78,0.97). Propranolol users had a significantly increased risk of PD (aRR:1.91; CI:1.20,3.06), whereas salbutamol use was associated with reduced risk of PD (aRR:0.95; CI:0.92,0.99). Significant heterogeneity (I² >87%) was observed, but the majority (n = 13) of the studies were of high quality, based on the JBI tool.
Beta-antagonist use was associated with a modestly increased risk of PD, whereas beta-agonist use was associated with a modest decreased risk of PD. Future epidemiological studies should address the issues of protopathic bias and indirect association using appropriate epidemiological methods.
Drug-induced tremor, clinical features, diagnostic approach and management
2022, Journal of the Neurological Sciences
Tremor is the most common movement disorder and there are numerous causes of tremor. In many individuals, tremor can be due to drugs. The most common drugs associated with tremor include amiodarone, selective serotonin (and norepinephrine) reuptake inhibitors (SSRIs/SNRIs), amitriptyline, lithium, valproate, β-adrenoceptor agonists, dopamine receptor antagonists, VMAT2 inhibitors, or drugs of abuse: ethanol, cocaine, etc. Drug-induced tremor usually resembles essential or parkinsonian tremor, depending on the offending drug; however, features such as unilateral, task-specific, position-dependent tremor or sudden onset, distractibility, entrainment and arrest with contralateral movements suggest etiologies such as dystonic or functional (psychogenic) tremor. Risk factors for drug-induced tremor include polypharmacy, male gender, older age, high doses and immediate-release preparations or reaching toxic levels of the offending drugs. Drug-induced tremor usually resolves once the offending medication is discontinued, however, persistent tremor may be observed in some cases (tardive tremor). In this manuscript, we discuss the most common causes of drug-induced tremor.
This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

View all citing articles on Scopus

^†: Authors contributed equally to this work

View full text

Rapid Reviewβ-adrenoreceptors and the risk of Parkinson's disease

Summary

Background

Recent developments

Where next?

Introduction

Section snippets

Proposed regulation of α-synuclein expression by β2-adrenoceptor agonists and antagonists

Biological function of the β-adrenoceptors

Epidemiological evidence of risk modulation with β-adrenoceptor acting drugs

Conclusions and future directions

Search strategy and selection criteria

Lancet Neurol

Parkinsonism Relat Disord

Parkinsonism Relat Disord

Neurochem Int

Lancet Neurol

Lancet

Lancet

J Am Coll Cardiol

Lancet

Mayo Clin Proc

Parkinsonism Relat Disord

Lancet Neurol

Parkinsonism Relat Disord

Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Lancet Neurol

The emerging evidence of the Parkinson pandemic

J Parkinsons Dis

Environment, lifestyle, and Parkinson's disease: implications for prevention in the next decade

Mov Disord

MDS research criteria for prodromal Parkinson's disease

Mov Disord

Advances in markers of prodromal Parkinson disease

Nat Rev Neurol

Meta-analysis of early nonmotor features and risk factors for Parkinson disease

Ann Neurol

Beta2-adrenoceptor agonists in parkinson's disease and other synucleinopathies

J Neuroimmune Pharmacol

targeting α-synuclein in Parkinson's disease: progress towards the development of disease-modifying therapeutics

Drugs

β2-adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease

Science

β2-adrenoceptor agonists and antagonists and risk of Parkinson's disease

Mov Disord

Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease

Neurology

Chronic use of β-blockers and the risk of parkinson's disease

Clin Drug Investig

β2-adrenoreceptor medications and risk of Parkinson disease

Ann Neurol

Alpha-synuclein in Lewy bodies

Nature

Zur pathologischen Anatomie der Paralysis Agitans

Dtsch Z Nervenheilkd

Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered

Mov Disord

Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension

Nat Med

Alpha- and beta-adrenergic receptor function in the brain during senescence

Neurobiol Aging

Beta-adrenergic receptors are involved in stress-related behavioral changes

Pharmacol Biochem Behav

Rapid Review
β-adrenoreceptors and the risk of Parkinson's disease