Samuel Sobarzo

Background: Parkinson’s disease is the second most common form of neurodegenerative disease in the United States.¹ Parkinson’s diseases can present with varying symptomatology, however some of the classical symptoms are bradykinesia, resting tremor, rigidity, and postural instability.¹ Pathologically Parkinson’s Disease is the loss of dopaminergic neurons in the substantia nigra pars compacta.¹ The loss dopaminergic neurons due to apoptosis, lead to an increase in the amount of available acetylcholine activity in the synaptic cleft. An escalation in cellular death can result in a corresponding rise in neuroinflammation. The current treatment for Parkinson’s disease targets the symptoms associated with Parkinson’s by replacing some of the diminished proteins.¹ Glucagon-like peptide-1 (GLP-1) is a naturally produced hormone, that is currently FDA approved in the treatment of diabetes, can cross the blood brain barrier and have potential effect on neuroinflammation.⁵ The field of halting Parkinson’s disease progression holds the potential for discovering novel therapeutic targets.

Objective: In the review, we investigated the use of Glucagon-like peptide-1 agonist to slow the progression of Parkinson’s disease and decrease the amount of neuroinflammation.

Search Methods: An online search through PubMed database was preformed from the time frame of 2018-2024, with the following keywords: “Glucagon-Like Peptide-1”, “Parkinson’s Disease”, “neuroinflammation”, “astrocytes”

Results: In an experiment preformed on mice, the effects of hyperglycemia and neuroinflammation was explored. The mice were kept at a chronically high level of serum glucose concentration, and then the level of microglial cells was quantified for the different mice.³ The high levels of serum glucose led to an increase in the systemic immune response, thus increasing the number of free-flowing cytokines systemic and in the brain. To continue to build on the insight, a controlled study has revealed that parkinsons patients have a significantly decreased amount of endogenously produced GLP-1 postprandial, particularly during the same meals. ⁵ The indication that GLP-1 has an effect on neuroinflammation was further investigated by checking the levels of intracranial inflammatory cytokines, after a GLP-1R was given to a mice with α-Synuclein pre-formed fibrils (PFF). The PFF mice showed a significant decrease in the TNF-α, C1q, and IL-1α cytokines when given GLP-1. ⁶ The effects that GLP-1R had on microglial activation were further researched, as an overexpression of microglial cells can contribute to death of healthy neurons. The microglial density was significantly decreased in the mouse that had received the GLP-1R.⁶ GLP-1R was identified in the reduction of tyrosine hydroxylase, which is the rate limiting step in dopamine synthesis.⁷

Conclusion: Studies have indicated that GLP-1R can decrease amount of neuroinflammation. Additionally, GLP-1R have shown to slow the progression of microglial cells into A1 toxic astrocytes, and clinically have shown to reduce the amount of tyrosine hydroxylase. Considerations for GLP-1R receptors would be if the decrease in these cytokines and prevention of conversion of cell type would influence the progression of Parkinson’s patients.

Work Cited:

• Erkkinen MG, Kim MO, Geschwind MD. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2018;10(4):a033118. Published 2018 Apr 2. doi:10.1101/cshperspect.a033118
• Chen SH, Chuang YC, Lin TK, Yang JL. Alternative role of glucagon-like Peptide-1 receptor agonists in neurodegenerative diseases. 2023;938:175439-175439. doi:https://doi.org/10.1016/j.ejphar.2022.175439
• Yisong Lv, Yuan L, Sun Y, et al. Long-term hyperglycemia aggravates α-synuclein aggregation and dopaminergic neuronal loss in a Parkinson’s disease mouse model. Translational neurodegeneration. 2022;11(1). doi:https://doi.org/10.1186/s40035-022-00288-z
• Brauer R , Wei L, Ma T, Athauda D, Girges C, Vijiaratnam N, Auld G, Whittlesea C, Wong I, Foltynie T. Diabetes medications and risk of Parkinson’s disease: a cohort study of patients with diabetes. Brain. 2020;143(10):3067-3076. doi:10.1093/brain/awaa262    Full text.‌
• Manfready RA, Engen PA, Verhagen Metman L, et al. Attenuated Postprandial  GLP-1 Response in Parkinson’s Disease. Front Neurosci. 2021;15:660942. Published 2021 Jul 2. doi:10.3389/fnins.2021.660942.   Full text.
• Yun SP , Kam TI, Panicker N, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med. 2018;24(7):931-938. doi:10.1038/s41591-018-0051-5 Full text.
• Chen S , Yu SJ, Li Y, et al. Post-treatment with PT302, a long-acting exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson’s disease. Scientific Reports. 2018;8(1). doi:10.1038/s41598-018-28449-z   Full text