GLP-1 Receptor Agonists show neuroprotective potential across diverse neurological disorders, but clinical translation faces BBB and trial design hurdles.

While Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established treatments for type 2 diabetes and obesity, their widespread distribution in the central nervous system (CNS) has opened avenues for repurposing them in neurological disorders. Current treatments for conditions like Alzheimer's and Parkinson's disease often fall short, highlighting an urgent need for novel neuroprotective strategies. The potential of GLP-1RAs stems from their ability to modulate key pathways implicated in neurodegeneration and inflammation, offering a promising therapeutic target.

This comprehensive review synthesized existing evidence on GLP-1 receptor agonists (GLP-1RAs) in neurological disorders, spanning both preclinical mechanisms and clinical trial outcomes. The authors surveyed studies across a broad range of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, intracerebral hemorrhage (ICH), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression, epilepsy, and spinal cord injury (SCI). The review critically assessed the main neuroprotective mechanisms and identified hurdles for successful clinical translation, particularly focusing on pharmacokinetic differences.

Preclinical studies consistently show that GLP-1RAs activate the cAMP/PKA/CREB pathway, boosting BDNF expression. They also engage the PI3K/Akt pathway, which inhibits GSK-3β and reduces tau hyperphosphorylation. Furthermore, these agonists suppress NLRP3 inflammasome activation in microglia and promote AMPK-dependent mitochondrial biogenesis and autophagy. In animal models of AD, PD, stroke, HD, MS, ALS, depression, epilepsy, and SCI, these cellular changes translated to reduced protein aggregation, decreased neuron loss, and improved functional outcomes. However, clinical data present a mixed picture, with some trials showing modest cognitive or motor improvements, while others found no significant effect on disease progression. The review highlights a critical factor: > Different GLP-1 receptor agonists cross the blood-brain barrier at widely varying rates, potentially explaining the inconsistent clinical trial results.