{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:53:48Z","timestamp":1785520428402,"version":"3.56.0"},"reference-count":115,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad de las Am\u00e9ricas","award":["592.A.XVII.25"],"award-info":[{"award-number":["592.A.XVII.25"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like peptide 1 (GLP-1) receptor agonists as potential disease-modifying agents. While several recent reviews have explored the role of incretin-based therapies, the present work provides an integrative perspective by combining a mechanistic analysis of GLP-1 signalling pathways with a model-specific synthesis of preclinical findings and an appraisal of clinical translational relevance. We consolidate evidence across PI3K\/Akt, MAPK\/ERK, cAMP\/PKA\u2013CREB, and AMPK pathways, emphasising their convergence on mitochondrial homeostasis, proteostasis, neuroinflammation, and synaptic resilience. To enhance translational clarity, we summarise preclinical studies across major PD models, evaluate dose comparability and blood\u2013brain barrier penetration, and identify pharmacokinetic and mechanistic factors that may explain divergent clinical outcomes. We also compare the therapeutic potential of key GLP-1 agonists, including exendin-4, liraglutide, semaglutide, lixisenatide, and emerging dual agonists. By integrating biochemical, preclinical, and clinical domains, this review provides a comprehensive framework for interpreting the current evidence and guiding the future development of incretin-based neuroprotective strategies in PD.<\/jats:p>","DOI":"10.3390\/ijms262412163","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T10:06:56Z","timestamp":1766052416000},"page":"12163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GLP-1 Signalling as a Therapeutic Avenue in Parkinson\u2019s Disease: A Comprehensive Review"],"prefix":"10.3390","volume":"26","author":[{"given":"Mar\u00eda Paz","family":"Orozco","sequence":"first","affiliation":[{"name":"NeurALL Research Group, Quito 170157, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Vintimilla Rivadeneira","sequence":"additional","affiliation":[{"name":"Cerebro, Emoci\u00f3n y Conduca (CEC) Research Group, Escuela de Medicina, Universidad de las Am\u00e9ricas (UDLA), Quito 170124, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8130-6460","authenticated-orcid":false,"given":"Jose E.","family":"Leon-Rojas","sequence":"additional","affiliation":[{"name":"Cerebro, Emoci\u00f3n y Conduca (CEC) Research Group, Escuela de Medicina, Universidad de las Am\u00e9ricas (UDLA), Quito 170124, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson Disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. 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