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
Rapid Reviewβ-adrenoreceptors and the risk of Parkinson's disease
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
References (65)
- et al.
The epidemiology of Parkinson's disease: risk factors and prevention
Lancet Neurol
(2016) - et al.
Calcium channel blockers and beta-blockers in relation to Parkinson's disease
Parkinsonism Relat Disord
(2007) - et al.
Autosomal dominant Parkinson's disease caused by SNCA duplications
Parkinsonism Relat Disord
(2016) - et al.
Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and [Ca(2+)]i
Neurochem Int
(2010) - et al.
Treatment of patients with essential tremor
Lancet Neurol
(2011) - et al.
Chronic obstructive pulmonary disease
Lancet
(2017) Migraine
Lancet
(2018)- et al.
Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015
J Am Coll Cardiol
(2017) - et al.
Heart failure
Lancet
(2017) Beta-blocker use for the stages of heart failure
Mayo Clin Proc
(2009)
Environmental risk factors and Parkinson's disease: an umbrella review of meta-analyses
Parkinsonism Relat Disord
Prediagnostic presentations of Parkinson's disease in primary care: a case-control study
Lancet Neurol
Essential tremor seems to be a risk factor for Parkinson's disease
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
Cited by (49)
Aporphines: A privileged scaffold in CNS drug discovery
2023, European Journal of Medicinal ChemistryTargeting G Protein-Coupled Receptors in the Treatment of Parkinson's Disease
2023, Journal of Molecular BiologyCitation 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.
Beta-adrenergic drugs and risk of Parkinson's disease: A systematic review and meta-analysis
2022, Ageing Research ReviewsCitation 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).
Drug-induced tremor, clinical features, diagnostic approach and management
2022, Journal of the Neurological Sciences
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Authors contributed equally to this work