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GLP-1 Receptor Agonists in Neurological Disorders: From Mechanisms to Clinical Translation
Pengpeng Li1, Yangyang Gao1, Wei Liu1
1Department of Neurosurgery, Xi'an Aerospace Hospital of Northwest University, Xi'an, Shanxi, 710000, People's Republic of China.
Drug Design, Development and Therapy
|June 18, 2026
Summary
Glucagon-like peptide-1 receptor agonists show promise for neurological disorders by protecting neurons through various cellular pathways. However, mixed clinical results highlight the need to optimize drug delivery across the blood-brain barrier for effective treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Endocrinology
Background:
- Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established treatments for type 2 diabetes and obesity.
- The presence of GLP-1 receptors in the central nervous system (CNS) suggests potential therapeutic applications for neurological disorders.
Purpose of the Study:
- To review the evidence for GLP-1RA repurposing in neurological conditions.
- To discuss the neuroprotective mechanisms of GLP-1RAs.
- To identify challenges for clinical translation.
Main Methods:
- Review of preclinical and clinical studies on GLP-1RAs in neurological diseases.
- Analysis of molecular pathways involved in neuroprotection.
- Examination of factors influencing blood-brain barrier penetration.
Main Results:
- Preclinical studies consistently show GLP-1RAs activate cAMP/PKA/CREB and PI3K/Akt pathways, reduce tau hyperphosphorylation, inhibit NLRP3 inflammasome, and promote mitochondrial biogenesis and autophagy.
- Animal models of various neurological diseases (e.g., Alzheimer's, Parkinson's, stroke) demonstrate reduced pathology and improved function with GLP-1RA treatment.
- Clinical trial results are mixed, potentially due to varying blood-brain barrier penetration rates among different GLP-1RAs.
Conclusions:
- GLP-1RAs exhibit significant neuroprotective potential via multiple cellular mechanisms.
- Clinical efficacy is hampered by inconsistent CNS drug levels, necessitating selection of BBB-penetrant agents.
- Future clinical success requires targeted drug selection, predictive biomarkers, and tailored trial designs for neurological conditions.
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