FRDA is a heritable neurodegenerative movement disorder fueled and exacerbated by neuroinflammation 290, 291, 292, which could make it a candidate for GLP-1R agonist treatment. Exenatide treatment was found to re-elevate reduced levels of frataxin, a critical mitochondrial protein, in FRDA patients, which can enhance mitochondrial health and function and could, by extension, reduce neuroinflammation and neurodegeneration characteristic of the disease [293]—again, providing a potentially fruitful area of future basic and clinical research. Similarly, studies by Meissner and colleagues [178] demonstrated the presence of impaired insulin/IGF-1 and IR in vulnerable brain regions of multiple system atrophy patients and a related transgenic mouse model, and their mitigation in the latter by exendin-4, likewise suggesting a promising area of future research.
Monday, November 14, 2022
Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Neuroinflammation: Implications for Neurodegenerative Disease Treatment
Katherine O. Kopp, Elliot J. Glotfelty, Yazhou Li, Nigel H. Greig; Pharmacological Research, 2022, 106550, DOI:10.1016/j.phrs.2022.106550.
Abstract: Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.
