Abstract
Parkinson’s disease (PD) is a neurodegenerative disease with increasing incidence in aged populations, second only to Alzheimer’s disease. Increasing evidence has shown that inflammation plays an important role in the occurrence and development of Parkinson’s disease. Growing evidence has shown that AMP-activated protein kinase (AMPK) and NF-κB are closely related to inflammation. Glucagon-like peptide 1 (GLP-1) is a hormone that is primarily secreted by intestinal endocrine L cells, and it has a variety of physiology through binding to GLP-1 receptor. GLP-1can be used for treatment of type 2 diabetes. In addition, GLP-1 also has anti-neuroinflammation activity. However, the exact mechanism behind how GLP-1 regulates neuroinflammation remains unclear. This study was designed to examine the effect of liraglutide on 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced injury in mice and its potential mechanism of action. Results showed that liraglutide dose-dependently ameliorated mouse behavior including swimming time and locomotor activity, increased the number of tyrosine hydroxylase (TH)-positive neurons and protein level, and reduced Iba1 and GFAP expression in the substantia nigra (SN). Liraglutide treatment also increased p-AMPK expression and reduced NF-κB protein level. Applying the AMPK inhibitor Dorsomorphin (Compound C) reversed the effect of liraglutide—reducing p-AMPK and increasing NF-κB expression. Finally, GFAP protein level increased, along with a decrease in TH expression. In conclusion, these results suggest that liraglutide can suppress neuroinflammation. Moreover, this effect is mediated through the AMPK/NF-κB signaling pathway.
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References
Abdelsalam RM, Safar MM (2015) Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways. J Neurochem 133:700–707
Aroda VR (2018) A review of GLP-1 receptor agonists: evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab 20(Suppl 1):22–33. https://doi.org/10.1111/dom.13162
Badawi GA, Abd El Fattah MA, Zaki HF, El Sayed MI (2017) Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson's disease. Inflammopharmacology 25:369–382
Beal MF (2001) Experimental models of Parkinson's disease. Nat Rev Neurosci 2(5):325–334. https://doi.org/10.1038/35072550
Brauer R, Wei L, Ma T, Athauda D, Girges C, Vijiaratnam N, Auld G, Whittlesea C, Wong I, Foltynie T (2020) Diabetes medications and risk of Parkinson's disease: a cohort study of patients with diabetes. Brain 143(10):3067–3076. https://doi.org/10.1093/brain/awaa262
Cantó C, Auwerx J (2009) PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20:98–105
Cantó C, Gerhart-Hines Z, Feige JN et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458:1056–1060
Chen A, Chen Z, Xia Y, Lu D, Yang X, Sun A, Zou Y, Qian J, Ge J (2018) Liraglutide attenuates NLRP3 inflammasome-dependent pyroptosis via regulating SIRT1/NOX4/ROS pathway in H9c2 cells. Biochem Biophys Res Commun 499(2):267–272. https://doi.org/10.1016/j.bbrc.2018.03.142
Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S (2015) Distribution and characterisation of glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab 4:718–731
Dickson DW. (2012) Parkinson's disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med 2
Donnan GA, Willis GL, Kaczmarczyk SJ, Rowe P (1987) Motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse. J Neurol Sci 77(2–3):185–191. https://doi.org/10.1016/0022-510x(87)90121-3
Dorsey ER, Elbaz A, Nichols E, Abd-Allah F, Abdelalim A, Adsuar JC, Ansha MG, Brayne C, Choi J-YJ, Collado-Mateo D, Dahodwala N, Do Huyen P, Edessa D, Endres M, Fereshtehnejad S-M, Foreman KJ, Gankpe FG, Gupta R, Hankey GJ et al (2018) Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 17(11):939–953. https://doi.org/10.1016/S1474-4422(18)30295-3
Elbaz A, Carcaillon L, Kab S, Moisan F (2016) Epidemiology of Parkinson's disease Rev Neurol (Paris) 172(1):14–26. https://doi.org/10.1016/j.neurol.2015.09.012
Fang Y, Jiang D, Wang Y et al (2018) Neuroprotection of rhGLP-1 in diabetic rats with cerebral ischemia/reperfusion injury via regulation of oxidative stress, EAAT2, and apoptosis. Drug Dev Res 79:249–259
Fang Q, Xicoy H, Shen J, Luchetti S, Dai D, Zhou P, Qi XR, Martens G, Huitinga I, Swaab DF, Liu C, Shan L (2021) Histamine-4 receptor antagonist ameliorates Parkinson-like pathology in the striatum. Brain Behav Immun 92:127–138. https://doi.org/10.1016/j.bbi.2020.11.036
Feng P, Zhang X, Li D, Ji C, Yuan Z, Wang R, Xue G, Li G, Hölscher C (2018) Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease. Neuropharmacology 133:385–394. https://doi.org/10.1016/j.neuropharm.2018.02.012
Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21:404–412
Ghosh A, Roy A, Liu X et al (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 104:18754–18759
Glotfelty EJ, Olson L, Karlsson TE, Li Y, Greig NH (2020) Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease. Expert Opin Investig Drugs 29(6):595–602. https://doi.org/10.1080/13543784.2020.1764534
Gong Z, Huang J, Xu B et al (2019) Urolithin a attenuates memory impairment and neuroinflammation in APP/PS1 mice. J Neuroinflammation 16:62
Graham DL, Durai HH, Trammell TS et al (2020) A novel mouse model of glucagon-like peptide-1 receptor expression: a look at the brain. J Comp Neurol 528:2445–2470
Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 26(1):6–17. https://doi.org/10.1002/mds.23455
Haobam R, Sindhu KM, Chandra G, Mohanakumar KP (2005) Swim-test as a function of motor impairment in MPTP model of Parkinson's disease: a comparative study in two mouse strains. Behav Brain Res 163(2):159–167. https://doi.org/10.1016/j.bbr.2005.04.011
Hinkle JT, Dawson VL, Dawson TM (2019) The A1 astrocyte paradigm: new avenues for pharmacological intervention in neurodegeneration. Mov Disord 34(7):959–969. https://doi.org/10.1002/mds.27718
Hirsch EC, Standaert DG (2021) Ten unsolved questions about Neuroinflammation in Parkinson's disease. Mov Disord 36(1):16–24. https://doi.org/10.1002/mds.28075
Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87(4):1409–1439. https://doi.org/10.1152/physrev.00034.2006
Hunter K, Hölscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33
Jensen CB, Pyke C, Rasch MG, Dahl AB, Knudsen LB, Secher A (2018) Characterization of the glucagonlike Peptide-1 receptor in male mouse brain using a novel antibody and in situ hybridization. Endocrinology 159:665–675
Jeon SM (2016) Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48:e245
Joers V, Tansey MG, Mulas G, Carta AR (2017) Microglial phenotypes in Parkinson's disease and animal models of the disease. Prog Neurobiol 155:57–75. https://doi.org/10.1016/j.pneurobio.2016.04.006
Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386(9996):896–912. https://doi.org/10.1016/S0140-6736(14)61393-3
Lee JA, Kim HR, Kim J, Park KD, Kim DJ, Hwang O (2018) The novel neuroprotective compound KMS99220 has an early anti-neuroinflammatory effect via AMPK and HO-1, independent of Nrf2. Exp Neurobiol 27:408–418
Lennox R, Flatt PR, Gault VA (2014) Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice. Peptides 61:38–47
Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH (2009) GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and parkinsonism. Proc Natl Acad Sci U S A 106(4):1285–1290. https://doi.org/10.1073/pnas.0806720106
Lin TK, Lin KJ, Lin HY, Lin KL, Lan MY, Wang PW, Wang TJ, Wang FS, Tsai PC, Liou CW, Chuang JH (2021) Glucagon-like Peptide-1 receptor agonist ameliorates 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) neurotoxicity through enhancing Mitophagy flux and reducing α-Synuclein and oxidative stress. Front Mol Neurosci 14:697440. https://doi.org/10.3389/fnmol.2021.697440
Liu W, Jalewa J, Sharma M, Li G, Li L, Hölscher C (2015) Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neuroscience 303:42–50
Lu M, Su C, Qiao C, Bian Y, Ding J, Hu G (2016) Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson's disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol 19
McGeer PL, McGeer EG (2008) Glial reactions in Parkinson's disease. Mov Disord 23(4):474–483. https://doi.org/10.1002/mds.21751
Na SJ, DiLella AG, Lis EV, Jones K, Levine DM, Stone DJ, Hess JF (2010) Molecular profiling of a 6-hydroxydopamine model of Parkinson's disease. Neurochem Res 35(5):761–772. https://doi.org/10.1007/s11064-010-0133-3
Nadkarni P, Chepurny OG, Holz GG (2014) Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci 121:23–65
Ou Z, Kong X, Sun X et al (2018) Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun 69:351–363
Ouchi Y (2017) Imaging neuroinflammation to monitor α-synucleinopathy. Lancet Neurol 16(10):763–764. https://doi.org/10.1016/S1474-4422(17)30244-2
Ouchi Y, Yoshikawa E, Sekine Y et al (2005) Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 57:168–175
Peixoto CA, Oliveira WH, Araújo S, Nunes A (2017) AMPK activation: role in the signaling pathways of neuroinflammation and neurodegeneration. Exp Neurol 298:31–41
Perry T, Lahiri DK, Chen D, Zhou J, Shaw KT, Egan JM, Greig NH (2002) A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther 300:958–966
Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, Greig NH (2003) Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res 72:603–612
Qin S, Tang H, Li W et al (2020) AMPK and its activator Berberine in the treatment of neurodegenerative diseases. Curr Pharm Des 26:5054–5066
Saito M, Saito M, Das BC (2019) Involvement of AMP-activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain. Int J Dev Neurosci 77:48–59
Schapira A, Chaudhuri KR, Jenner P (2017) Non-motor features of Parkinson disease. Nat Rev Neurosci 18(7):435–450. https://doi.org/10.1038/nrn.2017.62
Schmidt WE, Siegel EG, Creutzfeldt W (1985) Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 28:704–707
Sisson EM (2011) Liraglutide: clinical pharmacology and considerations for therapy. Pharmacotherapy 31(9):896–911. https://doi.org/10.1592/phco.31.9.896
Speciale SG (2002) MPTP: insights into parkinsonian neurodegeneration. Neurotoxicol Teratol 24(5):607–620. https://doi.org/10.1016/s0892-0362(02)00222-2
Stokholm MG, Iranzo A, Østergaard K et al (2017) Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol 16:789–796
Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ (2008) Synuclein activates microglia in a model of Parkinson's disease. Neurobiol Aging 29(11):1690–1701. https://doi.org/10.1016/j.neurobiolaging.2007.04.006
Wu AG, Zhou XG, Qiao G et al (2021) Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases. Ageing Res Rev 65:101202
Yoon G, Kim YK, Song J (2020) Glucagon-like peptide-1 suppresses neuroinflammation and improves neural structure. Pharmacol Res 152:104615
Yu W, Zha W, Ren J (2018) Exendin-4 and Liraglutide attenuate glucose toxicity-induced cardiac injury through mTOR/ULK1-dependent autophagy. Oxidative Med Cell Longev 2018:5396806. https://doi.org/10.1155/2018/5396806
Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Lee JH, Kumar M, An D et al (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med 24(7):931–938. https://doi.org/10.1038/s41591-018-0051-5
Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, Ruan Y, Xu A (2016) The neuroprotection of Liraglutide against Ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci Rep 6:26859. https://doi.org/10.1038/srep26859
Acknowledgments
This work was supported by grants from Science Foundation of Hebei Normal University (Grant Number L2020Z05), and Hebei Province Foundation for Returnees (Grant Number C20200341).
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Bing Cao was responsible for behavior test and immunofluorescence staining. Yanqiu Zhang was responsible for data analyze. Jinhu Chen was responsible for data visualization. Pengyue Wu was responsible for AMPK inhibition test. Yuxuan Dong was in charge of the fasting blood glucose test. Yanqin Wang was a major contributor in writing the manuscript.
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Cao, B., Zhang, Y., Chen, J. et al. Neuroprotective effects of liraglutide against inflammation through the AMPK/NF-κB pathway in a mouse model of Parkinson’s disease. Metab Brain Dis 37, 451–462 (2022). https://doi.org/10.1007/s11011-021-00879-1
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DOI: https://doi.org/10.1007/s11011-021-00879-1