საკვანძო სიტყვები
glucagon-like peptide
glp-1 agonists
semaglutide
როგორ უნდა ციტირება
ანოტაცია
Introduction
Drugs targeting insulin resistance in the brain have emerged as a potential therapeutic option for Parkinson's disease (PD). Their implication has originated from the studies indicating a link between Type 2 Diabetes Mellitus (T2DM) and PD, indicating that impairment in glucose and energy metabolism pathways contribute to the pathogenesis of PD. Owing to their potential neuroprotective properties in PD, glucagon-like peptide-1 (GLP-1) receptor agonists represent a category of antidiabetic medications that have garnered interest. The aim of this review is to evaluate the role of GLP-1 agonists as a novel treatment option for Parkinson’s disease concentrating on disease modifying effects.
Methods
The search of literature was performed in databases including PubMed, Google Scholar and ScienceDirect, the timeline applied was from years 2017 to 2025. Keywords used were “Parkinson's disease”, “glucagon-like peptide”, “glp-1 agonists”, “semaglutide”. Priority was set to peer-reviewed research, preclinical studies and clinical trials. References were screened for additional studies that could support the evidence.
Results
Data from preclinical and animal studies show, that GLP-1 agonists could modify the main pathological pathways impaired in Parkinson’s disease, including energy metabolism and neuroprotection. They improved the cell survival rate, autophagy stimulation, and reduced the apoptosis of mitochondria in cytotoxic in vitro cell models of PD and reduced the levels of alpha-synuclein in the brain in the mice models. Similarly, in rat model studies, incretin mimetics reduced pro-inflammatory cytokine levels, including TNFα, NF-kB and cyclooxygenase (COX1) and were able to regulate the function of microglial cells. GLP-1 agonists could improve dopaminergic transmission - they were shown to promote dopaminergic cell viability in substantia nigra pars compacta and normalize the tyrosine hydroxylase expression. Treatment with GLP-1 agonists have a positive impact on clinical features of PD. Marked improvement of motor function was seen as a result in the clinical trials, expressed by increase in MDS-UPDRS part III scales, as well as non-motor symptoms including cognition, mood and activities of daily living.
Conclusions
GLP-1 agonists show promise to have a disease modifying effect in Parkinson’s Disease by targeting factors like inflammation, insulin resistance, aiding in neuroprotection and improving motor and non-motor symptoms. As the existing knowledge gap renders making possible conclusions about the efficacy of these drugs in PD populations without insulin resistance and inflammation rather difficult, further research and clinical trials should be conducted to confirm or deny the same.
წყაროები
Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18(2):101-113. doi:10.1038/nrn.2016.178
Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91(8):795-808. doi:10.1136/jnnp-2019-322338
Gastrointestinal Autonomic Dysfunction in Patients with Parkinson’s Disease. Accessed March 9, 2025. https://e-jmd.org/journal/view.php?doi=10.14802/jmd.15008
Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560. doi:10.1001/jama.2019.22360
Hayes MT. Parkinson’s Disease and Parkinsonism. Am J Med. 2019;132(7):802-807. doi:10.1016/j.amjmed.2019.03.001
Nowell J, Blunt E, Edison P. Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease. Mol Psychiatry. 2023;28(1):217-229. doi:10.1038/s41380-022-01792-4
Crowley EK, Nolan YM, Sullivan AM. Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson’s disease: Evidence from rodent models. Prog Neurobiol. 2019;172:2-22. doi:10.1016/j.pneurobio.2018.11.003
Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat. 2008;4(4):743-757.
Jeong SH, Lee PH. Drug Repositioning and Repurposing for Disease-Modifying Effects in Parkinson’s Disease. J Mov Disord. 2025;18(2):113-126. doi:10.14802/jmd.25008
Hong CT, Chen JH, Hu CJ. Role of glucagon-like peptide-1 receptor agonists in Alzheimer’s disease and Parkinson’s disease. J Biomed Sci. 2024;31(1):102. doi:10.1186/s12929-024-01090-x
GLP-1 Elicits an Intrinsic Gut–Liver Metabolic Signal to Ameliorate Diet-Induced VLDL Overproduction and Insulin Resistance | Arteriosclerosis, Thrombosis, and Vascular Biology. Accessed March 8, 2025. https://www.ahajournals.org/doi/10.1161/ATVBAHA.117.310251
Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69-72. doi:10.1038/379069a0
Sc C, Je R, Mk H, Fm G, F R, S T. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10). doi:10.1016/j.molmet.2015.07.008
Zhang L, Zhang L, Li L, Hölscher C. Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson’s disease mouse model. Neuropeptides. 2018;71:70-80. doi:10.1016/j.npep.2018.07.003
Lv D, Feng P, Guan X, et al. Neuroprotective effects of GLP-1 class drugs in Parkinson’s disease. Front Neurol. 2024;15. doi:10.3389/fneur.2024.1462240
Early development of levodopa‐induced dyskinesias and response fluctuations in young‐onset Parkinson’s disease | Neurology. Accessed March 9, 2025. https://www.neurology.org/doi/10.1212/WNL.41.2_Part_1.202
Mild cognitive impairment in drug-naive patients with PD is associated with cerebral hypometabolism - PubMed. Accessed March 30, 2025. https://pubmed.ncbi.nlm.nih.gov/21940621/
Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites. Accessed April 7, 2025. https://www.mdpi.com/2227-9059/10/7/1582
High Prevalence of Undiagnosed Insulin Resistance in Non-Diabetic Subjects with Parkinson’s Disease - Elliot Hogg, Kishore Athreya, Christina Basile, Echo E. Tan, Jan Kaminski, Michele Tagliati, 2018. Accessed April 7, 2025. https://journals.sagepub.com/doi/full/10.3233/JPD-181305
Sánchez-Gómez A, Alcarraz-Vizán G, Fernández M, et al. Peripheral insulin and amylin levels in Parkinson’s disease. Parkinsonism Relat Disord. 2020;79:91-96. doi:10.1016/j.parkreldis.2020.08.018
Cullinane PW, de Pablo Fernandez E, König A, Outeiro TF, Jaunmuktane Z, Warner TT. Type 2 Diabetes and Parkinson’s Disease: A Focused Review of Current Concepts. Mov Disord. 2023;38(2):162-177. doi:10.1002/mds.29298
Dai C, Tan C, Zhao L, et al. Glucose metabolism impairment in Parkinson’s disease. Brain Res Bull. 2023;199:110672. doi:10.1016/j.brainresbull.2023.110672
The Association Between Type 2 Diabetes Mellitus and Parkinson’s Disease - Julia L.Y. Cheong, Eduardo de Pablo-Fernandez, Thomas Foltynie, Alastair J. Noyce, 2020. Accessed March 22, 2025. https://journals.sagepub.com/doi/full/10.3233/JPD-191900
Yue X, Li H, Yan H, Zhang P, Chang L, Li T. Risk of Parkinson Disease in Diabetes Mellitus: An Updated Meta-Analysis of Population-Based Cohort Studies. Medicine (Baltimore). 2016;95(18):e3549. doi:10.1097/MD.0000000000003549
Rhee SY, Han KD, Kwon H, et al. Association Between Glycemic Status and the Risk of Parkinson Disease: A Nationwide Population-Based Study. Diabetes Care. 2020;43(9):2169-2175. doi:10.2337/dc19-0760
Pagano G, Polychronis S, Wilson H, et al. Diabetes mellitus and Parkinson disease. Neurology. 2018;90(19). doi:10.1212/WNL.0000000000005475
Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153-165. doi:10.1016/j.cmet.2006.01.004
Holst JJ. The Physiology of Glucagon-like Peptide 1. Physiol Rev. 2007;87(4):1409-1439. doi:10.1152/physrev.00034.2006
Drucker DJ. Glucagon-Like Peptide-1 and the Islet β-Cell: Augmentation of Cell Proliferation and Inhibition of Apoptosis. Endocrinology. 2003;144(12):5145-5148. doi:10.1210/en.2003-1147
McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJ. Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation. Endocr Rev. 2021;42(2):101-132. doi:10.1210/endrev/bnaa032
Laurindo LF, Barbalho SM, Guiguer EL, et al. GLP-1a: Going beyond Traditional Use. Int J Mol Sci. 2022;23(2):739. doi:10.3390/ijms23020739
Kabahizi A, Wallace B, Lieu L, et al. Glucagon-like peptide-1 (GLP-1) signalling in the brain: From neural circuits and metabolism to therapeutics. Br J Pharmacol. 2022;179(4):600-624. doi:10.1111/bph.15682
Mayendraraj A, Rosenkilde MM, Gasbjerg LS. GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation. Peptides. 2022;151:170749. doi:10.1016/j.peptides.2022.170749
Cornell S. A review of GLP‐1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once‐weekly agents. J Clin Pharm Ther. 2020;45(S1):17-27. doi:10.1111/jcpt.13230
Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res. 2022;186:106550. doi:10.1016/j.phrs.2022.106550
Liu DX, Zhao CS, Wei XN, Ma YP, Wu JK. Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress. Park Dis. 2022;2022:6813017. doi:10.1155/2022/6813017
Zhang L, Zhang ,Wen, and Tian X. The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. Int J Neurosci. 2023;133(5):473-491. doi:10.1080/00207454.2021.1924707
Mahapatra MK, Karuppasamy M, Sahoo BM. Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review. Pharm Res. 2022;39(6):1233-1248. doi:10.1007/s11095-022-03302-1
Zhang L, Li C, Zhang Z, et al. DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model. Park Dis. 2022;2022:1428817. doi:10.1155/2022/1428817
Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol. 2021;20(1):189. doi:10.1186/s12933-021-01366-8
Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer’s and Parkinson’s disease therapeutics. Biochem Pharmacol. 2020;180:114187. doi:10.1016/j.bcp.2020.114187
Ferrari F, Moretti A, Villa RF. Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives. Pharmacol Ther. 2022;239:108277. doi:10.1016/j.pharmthera.2022.108277
Pajares M, I. Rojo A, Manda G, Boscá L, Cuadrado A. Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. Cells. 2020;9(7):1687. doi:10.3390/cells9071687
The Role of Oxidative Stress in Parkinson’s Disease - Vera Dias, Eunsung Junn, M. Maral Mouradian, 2013. Accessed April 7, 2025. https://journals.sagepub.com/doi/abs/10.3233/JPD-130230
Erekat NS. Apoptosis and its Role in Parkinson’s Disease. In: Stoker TB, Greenland JC, eds. Parkinson’s Disease: Pathogenesis and Clinical Aspects. Codon Publications; 2018. Accessed April 7, 2025. http://www.ncbi.nlm.nih.gov/books/NBK536724/
Athauda D, Foltynie T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today. 2016;21(5):802-818. doi:10.1016/j.drudis.2016.01.013
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. doi:10.1038/42166
Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14(1):38-48. doi:10.1038/nrn3406
Lv M, Xue G, Cheng H, et al. The GLP-1/GIP dual-receptor agonist DA5-CH inhibits the NF-κB inflammatory pathway in the MPTP mouse model of Parkinson’s disease more effectively than the GLP-1 single-receptor agonist NLY01. Brain Behav. 2021;11(8):e2231. doi:10.1002/brb3.2231
Kalinderi K, Papaliagkas V, Fidani L. GLP-1 Receptor Agonists: A New Treatment in Parkinson’s Disease. Int J Mol Sci. 2024;25(7):3812. doi:10.3390/ijms25073812
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
Géa LP, da Rosa ED, Panizzutti BS, et al. Reduction of hippocampal IL-6 levels in LPS-injected rats following acute exendin-4 treatment. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(7):1303-1311. doi:10.1007/s00210-020-01867-5
Aksoy D, Solmaz V, Çavuşoğlu T, Meral A, Ateş U, Erbaş O. Neuroprotective Effects of Eexenatide in a Rotenone-Induced Rat Model of Parkinson’s Disease. Am J Med Sci. 2017;354(3):319-324. doi:10.1016/j.amjms.2017.05.002
Wu HY, Tang XQ, Mao XF, Wang YX. Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial β-Endorphin Expression. J Neurosci Off J Soc Neurosci. 2017;37(48):11701-11714. doi:10.1523/JNEUROSCI.1799-17.2017
Grieco M, Giorgi A, Gentile MC, et al. Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases. Front Neurosci. 2019;13:1112. doi:10.3389/fnins.2019.01112
Dauer W, Przedborski S. Parkinson’s Disease: Mechanisms and Models. Neuron. 2003;39(6):889-909. doi:10.1016/S0896-6273(03)00568-3
Guillot TS, Miller GW. Protective Actions of the Vesicular Monoamine Transporter 2 (VMAT2) in Monoaminergic Neurons. Mol Neurobiol. 2009;39(2):149-170. doi:10.1007/s12035-009-8059-y
Fazio P, Svenningsson P, Cselényi Z, Halldin C, Farde L, Varrone A. Nigrostriatal dopamine transporter availability in early Parkinson’s disease. Mov Disord. 2018;33(4):592-599. doi:10.1002/mds.27316
Wu RM, Cheng CW, Chen KH, et al. The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. Neurology. 2001;56(3):375-382. doi:10.1212/WNL.56.3.375
Löhle M, Mangone G, Wolz M, et al. Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson’s disease. Mov Disord. 2018;33(9):1496-1501. doi:10.1002/mds.27466
Semaglutide is Neuroprotective and Reduces α-Synuclein Levels in the Chronic MPTP Mouse Model of Parkinson’s Disease. doi:10.3233/JPD-181503
Dahiya S, Tisch S, Greenfield J. The effect of GLP-1 receptor agonists in pre-clinical rodent models of Parkinson’s disease: A systematic review and meta-analysis. Clin Park Relat Disord. 2022;6:100133. doi:10.1016/j.prdoa.2022.100133
Zhang L, Zhang W, Tian X. The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. Int J Neurosci. 2023;133(5):473-491. doi:10.1080/00207454.2021.1924707
Chen SD, Chuang YC, Lin TK, Yang JL. Alternative role of glucagon-like Peptide-1 receptor agonists in neurodegenerative diseases. Eur J Pharmacol. 2023;938:175439. doi:10.1016/j.ejphar.2022.175439
Yamamoto H, Kishi T, Lee CE, et al. Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. J Neurosci Off J Soc Neurosci. 2003;23(7):2939-2946. doi:10.1523/JNEUROSCI.23-07-02939.2003
Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J Neuroinflammation. 2008;5(1):19. doi:10.1186/1742-2094-5-19
Malatt C, Wu T, Bresee C, et al. Liraglutide Improves Non-Motor Function and Activities of Daily Living in Patients with Parkinson’s disease: A Randomized, Double-Blind, Placebo-Controlled Trial (P9-11.005). Neurology. 2022;98(18_supplement):3068. doi:10.1212/WNL.98.18_supplement.3068
Meissner WG, Remy P, Giordana C, et al. Trial of Lixisenatide in Early Parkinson’s Disease. N Engl J Med. 2024;390(13):1176-1185. doi:10.1056/NEJMoa2312323
Tan X, Cao ,Xiaojing, Zhou ,Minzhi, Zou ,Ping, and Hu J. Efficacy and safety of once-weekly semaglutide for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2017;26(9):1083-1089. doi:10.1080/13543784.2017.1360274
Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev. 2019;20(6):805-815. doi:10.1111/obr.12839
Seino Y, Terauchi Y, Osonoi T, et al. Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes. Diabetes Obes Metab. 2018;20(2):378-388. doi:10.1111/dom.13082
O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. The Lancet. 2018;392(10148):637-649. doi:10.1016/S0140-6736(18)31773-2
Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(5):355-366. doi:10.1016/S2213-8587(17)30085-2
Sorli C, Harashima S ichi, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-260. doi:10.1016/S2213-8587(17)30013-X
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | New England Journal of Medicine. Accessed March 27, 2025. https://www.nejm.org/doi/10.1056/NEJMoa1607141
Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial - PubMed. Accessed March 3, 2025. https://pubmed.ncbi.nlm.nih.gov/28781108/
Hogg E, Wu T, Bresee C, et al. A Phase II, Randomized, Double-Blinded, Placebo-Controlled Trial of Liraglutide in Parkinson’s Disease. SSRN Electron J. Published online 2022. doi:10.2139/ssrn.4212371
Trial of Lixisenatide in Early Parkinson’s Disease - PubMed. Accessed March 3, 2025. https://pubmed.ncbi.nlm.nih.gov/38598572/