Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges
Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T...
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Elsevier
2025-06-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825001951 |
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| author | Zhi Dong Zhou Lingxiao Yi Karolina Popławska-Domaszewicz Kallol Ray Chaudhuri Joseph Jankovic Eng King Tan |
| author_facet | Zhi Dong Zhou Lingxiao Yi Karolina Popławska-Domaszewicz Kallol Ray Chaudhuri Joseph Jankovic Eng King Tan |
| author_sort | Zhi Dong Zhou |
| collection | DOAJ |
| description | Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects. |
| format | Article |
| id | doaj-art-bcd52fb812eb4d629c85a8fc11fca72b |
| institution | OA Journals |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-bcd52fb812eb4d629c85a8fc11fca72b2025-08-20T02:32:20ZengElsevierPharmacological Research1096-11862025-06-0121610777010.1016/j.phrs.2025.107770Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challengesZhi Dong Zhou0Lingxiao Yi1Karolina Popławska-Domaszewicz2Kallol Ray Chaudhuri3Joseph Jankovic4Eng King Tan5National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, SingaporeNational Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, SingaporeDepartment of Neurology, Poznan University of Medical Sciences, Poznan 60-355, Poland; Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London SE5 9RS, UKDepartment of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King's College London, Cutcombe Road, London SE5 9RT, UKParkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USANational Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore; Correspondence to: Department of Neurology, National Neuroscience Institute of Singapore (Singapore General Hospital campus), Outram Road, 169608, Singapore.Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.http://www.sciencedirect.com/science/article/pii/S1043661825001951Glucagon-like peptide-1GLP-1 receptor agonistsNeurodegenerative diseasesAlzheimer’s diseaseParkinsons' diseaseType 2 diabetes mellitus |
| spellingShingle | Zhi Dong Zhou Lingxiao Yi Karolina Popławska-Domaszewicz Kallol Ray Chaudhuri Joseph Jankovic Eng King Tan Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges Pharmacological Research Glucagon-like peptide-1 GLP-1 receptor agonists Neurodegenerative diseases Alzheimer’s disease Parkinsons' disease Type 2 diabetes mellitus |
| title | Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges |
| title_full | Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges |
| title_fullStr | Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges |
| title_full_unstemmed | Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges |
| title_short | Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges |
| title_sort | glucagon like peptide 1 receptor agonists in neurodegenerative diseases promises and challenges |
| topic | Glucagon-like peptide-1 GLP-1 receptor agonists Neurodegenerative diseases Alzheimer’s disease Parkinsons' disease Type 2 diabetes mellitus |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825001951 |
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