Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges

May 9, 2025Pharmacological research

Potential and challenges of glucagon-like peptide-1 receptor activators in treating brain diseases that cause memory and movement loss

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Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists may improve motor deficits in Parkinson's disease patients and cognitive function in Alzheimer's disease patients.

GLP-1 receptor agonists reduce blood glucose and energy intake by mimicking the actions of the incretin hormone GLP-1.
Patients with type 2 diabetes have a higher risk of developing neurodegenerative diseases, potentially linked to insulin signaling issues.
Experimental studies suggest GLP-1 receptor agonists may protect against neuroinflammation, oxidative stress, and protein misfolding.
Clinical trials show that exenatide, liraglutide, and lixisenatide can improve symptoms in Parkinson's disease patients.
Liraglutide may enhance cognitive function in Alzheimer's disease patients.
Benefits of GLP-1 receptor agonists in neurodegenerative diseases are still being explored, including their use in combinations with other drugs.

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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.

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Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges

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