Review
Keynote
The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action

https://doi.org/10.1016/j.drudis.2016.01.013Get rights and content
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open access

Highlights

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    GLP-1 analogs can cross the blood–brain barrier and stimulate the GLP-1 receptor in the brain.

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    Stimulation of the GLP-1 receptor has shown effects on mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning and memory in multiple experimental models of PD and AD.

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    Parkinson's disease and type 2 diabetes share many common pathophysiological mechanisms.

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    A process analogous to peripheral insulin resistance may initiate/exacerbate neurodegeneration in PD.

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    Restoration of brain insulin sensitivity is one possible explanation for the neuroprotective effects seen in models of PD and AD.

Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD).

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Dilan Athauda is a specialist registrar in neurology and a clinical research fellow in the Department of Functional Neurosurgery at the National Hospital for Neurology and Neurosurgery, Queen Square, London, investigating disease-modifying therapy in Parkinson's disease (PD). He graduated from King's College, London, and is currently a subinvestigator for a trial of exenatide, a GLP-1 agonist in PD.

Tom Foltynie is senior lecturer and honorary consultant neurologist at the Sobell Department of Motor Neuroscience at the UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London. He completed neurology training at Cambridge University, where he undertook his PhD in the epidemiology & genetics of PD. He is chief investigator for a trial of exenatide, a potential neurorestorative treatment for PD, as well as the lead clinician at UCL for a multicentre trial of foetal dopaminergic cell transplantation for PD, and a proposed trial of deep brain stimulation (DBS) as a treatment for the cognitive problems associated with advanced PD. Dr Foltynie is also leading a trial of DBS for the treatment of patients with severe Tourette syndrome. Aside from trial involvement, patients with PD and without DBS are being recruited to research looking at the influence of genetics on PD risk and clinical progression, and the use of functional imaging to explore the mechanism of action of DBS surgery.

© 2016 The Authors. Published by Elsevier Ltd.