Beyond glycemic control: Uncovering the neuroprotective role of GLP-1 receptor agonists

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for type 2 diabetes mellitus and obe- sity, are emerging as neuroprotective candidates in neurological disorders [1,2]. This lecture provides a mechanistic overview of their central nervous system (CNS) actions. Methods: Literature review focused on GLP-1 RAs pharmacol- ogy, intracellular signaling and downstream pathways relevant to neuroprotection. Results: GLP-1 receptors are broadly expressed in CNS and their activation engages cyclic AMP-dependent and phosphoinosit- ide 3-kinase signaling, producing pleiotropic effects [3,4]: (i) at- tenuation of neuroinflammation via microglial polarization to anti-inflammatory phenotype, NFkB and NLRP3 inflammasome inhibition, suppression of TNF-alpha, IL-1-beta and IL-6, and prevention of neurotoxic reactive astrocyte conversion; (ii) anti- apoptotic activity through Bcl-2 upregulation and Bax/caspase-3 suppression; (iii) mitochondrial biogenesis via PGC-1-alpha and sirtuin-1, with reduction of oxidative stress; (iv) neurotrophic and synaptic support through brain-derived neurotrophic factor/TrkB signaling, AMPA receptor trafficking, postsynaptic density pro- tein-95 upregulation, hippocampal neurogenesis and long-term potentiation; (v) proteostasis restoration via ULK1-dependent autophagy, reducing amyloid-beta, hyperphosphorylated tau and alfa-synuclein aggregates; (vi) preservation of blood-brain barrier and neurovascular unit. Additional body-to-brain signaling via vagal afferents contributes to indirect central neuroprotection. Conclusion: GLP-1 RAs display multifaceted, converging neuro- protective mechanisms targeting the triad of neurodegeneration: neuroinflammation, mitochondrial dysfunction and proteinop- athy. Their established safety profile and pleiotropy make them strong candidates for repurposing in neurology. References: [1] Ferrari et al. (2022). Pharmacol Ther. 239:108277; [2] Ferrari et al. (2020). Pharmacol Res. 160:105018; [3] Ros-Madrid et al. (2025). Can J Physiol Pharmacol. 103:369– 377; [4] Roy et al. (2025). Neurotherapeutics. 22:e00712. Disclosure: The author declares no conflicts of interest.