Novel drug delivery systems of β2 adrenoreceptor agonists to suppress SNCA gene expression and mitochondrial oxidative stress in Parkinson’s disease management

ABSTRACT

Introduction

α-synuclein (SNCA), a major component of Lewy body is a pathological hallmark of Parkinson’s disease (PD). Mutations in the SNCA gene cause misfolding and aggregation of SNCA protein, which results in neurodegeneration. Several studies have established the neuroprotective benefits of β2-adrenoreceptor (β2AR) agonists in PD However, β2AR agonists are associated with peripheral side effects- tachycardia, palpitation, pulmonary edema, myocardial ischemia, and cardiac arrhythmia due to βARactivation in peripheral tissues. PD therapy with β2AR agonists, therefore, warrants a brain-specific delivery.

Area covered

This review highlights the SNCA mediated neurodegenerative pathways in PD and various treatment strategies under investigation to lower SNCA gene expression, primarily focusing on β2AR mediated pathway. The review also discusses the beneficial and side effects of β2AR agonists in PD treatment by reviewing clinical trials, epidemiological studies, and meta-analysis data. Here we depict the need to develop a novel drug delivery system to achieve brain-specific delivery of β2AR agonists to overcome peripheral side effects and also propose various nano delivery strategies to achieve the same.

Expert opinion

Brain targeted delivery of β2AR agonists via various nano delivery systems will significantly downregulate SNCA gene expression in PD and also overcomes peripheral side effects of β2AR agonists.

KEYWORDS:

• Α-synuclein (SNCA)
• β2-adrenoreceptor (β2AR) agonists
• blood-brain barrier (BBB)
• parkinson’s disease (PD)
• solid Lipid Nanoparticles (SLNs)
• polymeric Nanoparticles (PNPs)
• carbon Nanotubes (CNTs)

Article highlights

• Neurodegeneration drives the disease progression in PD, leading to life-threatening complications such as depression, dysphagia, or difficulty in swallowing, cognitive impairment, sleep disorders, etc.

• The abnormal Lewy bodies, mainly composed of SNCA, is the hallmark of PD and is responsible for neurodegeneration and disease progression in PD.

• None of the current anti-parkinsonian therapies can halt disease progression mediated by SNCA pathologies.

• Brain β2-receptor activation through β2-receptor agonists can decrease the SNCA gene expression and hence prevent disease progression mediated by SNCA pathologies.

• β-receptor activation in the peripheral tissues produces off-target side effects such as tachycardia, palpitation, pulmonary edema, myocardial ischemia, and cardiac arrhythmia.

• Polymeric nanoparticles, liposomes, dendrimers, micelles, solid lipid nanoparticles, and carbon-nanotubes loaded with β2AR agonists and surface modified with brain targeting agents like tween-80, transferring, OX-26, lactoferrin, folic acid, etc., can achieve brain-specific drug delivery with improved therapeutic efficacy and reduced off-target side effects.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors would like to thank the Department of Science and Technology- Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi, for their infrastructure support to our department (Grant No. SR/FST/LSI-574/2013).