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Alternative role of glucagon-like Peptide-1 receptor agonists in neurodegenerative diseases
Shang-Der Chen1, Yao-Chung Chuang2, Tsu-Kung Lin3
1Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan.
Abstract:
Aging is a crucial risk factor for common neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Limited options are available for the treatment of age-related, multiple pathogenic mechanism-contributed diseases that usually advance to irreversible conditions with severe neurological deficits and result in a heavy socioeconomic burden on patients, families, and society. A therapy that decelerates disease progression and reduces the socioeconomic burden stemming from these diseases is required. Glucagon-like peptide-1 receptor (GLP-1R) is an important class of medication for type 2 diabetes mellitus (T2DM). Through pancreatic effects, GLP-1R agonists can stimulate insulin secretion, increase β-cell proliferation, reduce β-cell apoptosis, and inhibit glucagon secretion in patients with T2DM. Currently, seven clinically approved GLP-1R agonists are used for T2DM: exenatide, liraglutide, lixisenatide, extended-release exenatide, albiglutide, dulaglutide, and semaglutide. Besides the pancreas, GLP-1Rs are also expressed in organs, such as the gastrointestinal tract, heart, lung, kidney, and brain, indicating their potential use in diseases other than T2DM. Emerging evidence reveals that GLP-1R agonists possess pleiotropic effects that enrich neurogenesis, diminish apoptosis, preclude neurons from oxidative stress, and reduce neuroinflammation in various neurological conditions. These favorable effects may also be employed in neurodegenerative diseases. Herein, we reviewed the recent progress, both in preclinical studies and clinical trials, regarding these clinically used GLP-1R agonists in aging-related neurodegenerative diseases, mainly AD and PD. We stress the pleiotropic characteristics of GLP-1R agonists as repurposing drugs to target multiple pathological mechanisms and for use in the future for these devastating neurodegenerative conditions.
Insights
Glucagon-like peptide-1 receptor (GLP-1R) agonists, used for type 2 diabetes, show promise in treating neurodegenerative diseases like Alzheimer's and Parkinson's. These drugs offer neuroprotective benefits, potentially slowing disease progression and reducing patient burden.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Aging is a primary risk factor for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).
- Current treatments for these age-related conditions are limited, often failing to halt irreversible neurological deficits and imposing significant socioeconomic burdens.
- Glucagon-like peptide-1 receptor (GLP-1R) agonists are established medications for type 2 diabetes mellitus (T2DM), with known pancreatic effects.
Purpose of the Study:
- To review the potential of clinically approved GLP-1R agonists in treating aging-related neurodegenerative diseases, primarily AD and PD.
- To highlight the pleiotropic, neuroprotective effects of GLP-1R agonists beyond their metabolic functions.
- To assess the progress of these drugs in preclinical studies and clinical trials for neurodegenerative conditions.
Main Methods:
- Literature review of preclinical studies and clinical trials.
- Analysis of the expression of GLP-1 receptors in the brain and other organs.
- Examination of the neuroprotective mechanisms of GLP-1R agonists, including neurogenesis, anti-apoptosis, antioxidant, and anti-inflammatory effects.
Main Results:
- GLP-1 receptors are expressed in the brain, suggesting direct neurological effects.
- GLP-1R agonists demonstrate pleiotropic effects beneficial for neurological health, such as promoting neurogenesis and reducing neuroinflammation.
- Evidence from preclinical and clinical studies indicates potential therapeutic benefits of GLP-1R agonists in AD and PD models.
Conclusions:
- GLP-1R agonists possess multifaceted neuroprotective properties applicable to neurodegenerative diseases.
- Repurposing GLP-1R agonists offers a promising strategy to target multiple pathological mechanisms in AD and PD.
- These drugs represent a potential future therapeutic avenue for devastating neurodegenerative conditions, aiming to decelerate progression and alleviate patient burden.
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