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Cited by 136Parkinson's Disease Mechanisms and TreatmentsDiabetes Treatment and ManagementAlzheimer's disease research and treatments

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A New Treatment Strategy for Parkinson's Disease through the Gut–Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway

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Kim, Dong Seok, Choi, Ho-Il, Wang, Yun, Luo, Yu, Hoffer, Barry J., Greig, Nigel H.·2017·Cell Transplantation
DOI 10.1177/0963689717721234PMC PMC5680957
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Abstract

Molecular communications in the gut–brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut–brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut–brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long-lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut–brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor.

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Fig. 1. Proposed mechanisms underpinning the beneficial neurological action of glucagon-like peptide-1 (GLP-1) receptor (R) agonists. The GLP-1R, a class B1 G-protein-coupled receptor, is present on numerous cells within the nervous system—including throughout the brain on multiple types of neurons as well as on astrocytes and microglia. GLP-1, chiefly generated by L cells within the gastrointestinal tract, is also produced by select preproglucagon neurons that are primarily localized to the nucleus of the solitary tract within the hind brain87—providing projections to extensive brain areas. Notably, GLP-1 appears also be generated by M2 microglia88 to potentially provide reparative/anti-inflammatory actions. Endogenous GLP-1 and/or long-acting GLP-1 agonists gaining access to the brain can provide neurotrophic/protective actions that are mediated via GLP-1R binding and activation (as such actions are lost in the presence of GLP-1R antagonists and in GLP-1R knockout studies35,89,90). Stimulation of the GLP-1R results to a rapid rise in intracellular cAMP levels, which then activates protein kinase A and phosphoinositide 3-kinase (PI3K); phosphorylating and activating a variety of downstream signalling pathways. These can be broadly subdivided into 2 divisons: the mitogen-associated protein kinase/extracellular signal–regulated kinase and PI3K/protein kinase B pathways. These modulate multiple intracellular events including augmenting protein synthesis, cellular proliferation (neurogenesis), mitochondrial biogenesis and inhibiting apoptosis, inflammation, and protein aggregation. Both singly and in combination these pathways can lead to improved cell survival and a more robust cellular phenoype. cAMP, cyclic AMP; CREB, cAMP response element-binding protein; FoxO1/O3, forkhead box O1/O3; GSK-3β, glycogen synthase 3 β; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.
Fig. 1. Proposed mechanisms underpinning the beneficial neurological action of glucagon-like peptide-1 (GLP-1) receptor (R) agonists. The GLP-1R, a class B1 G-protein-coupled receptor, is present on numerous cells within the nervous system—including throughout the brain on multiple types of neurons as well as on astrocytes and microglia. GLP-1, chiefly generated by L cells within the gastrointestinal tract, is also produced by select preproglucagon neurons that are primarily localized to the nucleus of the solitary tract within the hind brain87—providing projections to extensive brain areas. Notably, GLP-1 appears also be generated by M2 microglia88 to potentially provide reparative/anti-inflammatory actions. Endogenous GLP-1 and/or long-acting GLP-1 agonists gaining access to the brain can provide neurotrophic/protective actions that are mediated via GLP-1R binding and activation (as such actions are lost in the presence of GLP-1R antagonists and in GLP-1R knockout studies35,89,90). Stimulation of the GLP-1R results to a rapid rise in intracellular cAMP levels, which then activates protein kinase A and phosphoinositide 3-kinase (PI3K); phosphorylating and activating a variety of downstream signalling pathways. These can be broadly subdivided into 2 divisons: the mitogen-associated protein kinase/extracellular signal–regulated kinase and PI3K/protein kinase B pathways. These modulate multiple intracellular events including augmenting protein synthesis, cellular proliferation (neurogenesis), mitochondrial biogenesis and inhibiting apoptosis, inflammation, and protein aggregation. Both singly and in combination these pathways can lead to improved cell survival and a more robust cellular phenoype. cAMP, cyclic AMP; CREB, cAMP response element-binding protein; FoxO1/O3, forkhead box O1/O3; GSK-3β, glycogen synthase 3 β; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.CC BY-NC · PubMed Central

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Research works printed but not linked: 3

  1. Guo LX, 2009, Chin Med J (Engl), 122, 2886
  2. Puddu A, 2013, Mediators Inflamm, 317120
  3. Heikkila RE, 1987, Adv Neurol, 45, 149

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Metadata

Authors
Kim, D. S., Choi, H.-I., Wang, Y., Luo, Y., Hoffer, B. J., & Greig, N. H.
Affiliations
  • National Institutes of Health (US)
  • Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea
  • National Health Research Institutes (TW)
  • Case Western Reserve University (US)
Corresponding author
  • Kim, Dong Seok
  • Greig, Nigel H.
ORCID
Venue
Cell Transplantation
Publisher
SAGE Publications
Published
2017-09
Volume
26
Issue
9
Pages
1560-1571
ISSN
  • 0963-6897 (ISSN-L)
  • 1555-3892
DOI
10.1177/0963689717721234
PMC
PMC5680957
OpenAlex
W2609107212
Cited by
136
References
113
Citations by year
2025: 12 · 2024: 15 · 2023: 15 · 2022: 29 · 2021: 20 · 2020: 19 · 2019: 14 · 2018: 10 · 2017: 2
FWCI
1.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Transplantation (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (R01NS094152)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
Parkinson's disease, gut-brain axis, GLP-1 receptor agonists, exenatide, type 2 diabetes, neurodegenerative diseases, neuroprotection, aging, DPP-4 inhibitors, oxidative stress, inflammation, insulin resistance, motor and cognitive function
MeSH terms
Glucagon-Like Peptide-1 Receptor, Exenatide, Animals, Blood Glucose, Humans, Hypoglycemic Agents, Parkinson Disease, Peptides, Venoms, Neuroprotective Agents, Glucagon-Like Peptide 1

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