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The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action
Open accessAbstract
Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD).
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“Glucagon-like peptide-1 (GLP-1) is an endogenous hormone secreted by ileal endocrine cells, which promotes insulin secretion in a hyperglycemic environment (Athauda and Foltynie 2016).”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Athauda and Foltynie 2016
In the citing paper
“GLP-1 is an enterogenous hormone that promotes insulin secretion and reduces glucagon secretion to reduce blood glucose in a glucose concentration-dependent manner (Athauda and Foltynie 2016).”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Athauda and Foltynie 2016
In the citing paper
“However, as GLP-1 is easily degraded, continuous intravenous drip or continuous subcutaneous injection is required to produce therapeutic effects, which limits its clinical usage.”
From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Athauda and Foltynie 2016
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Self-citationGLP-1 Receptor Agonists: Beyond Their Pancreatic Effects
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“In advanced Parkinson's diseases (PD), Alzheimer's diseases (AD), Huntington's disease HD), DM, cardiovascular diseases (CVD), and other age-related diseases, insulin resistance effects are observed [4, 5].”
BackgroundGlucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases
Grieco, M., Giorgi, A., Gentile, M. C., d’Erme, M., Morano, S., Maras, B., & Filardi, T. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01112 · Cited by 218
The Antidepressant Effects of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis
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“One such GLP1R agonist, NLY01, was shown to be neuroprotective in PD models by specifically regulating NF-κB-mediated inflammatory signaling which is downstream of the GLP-1R/PI3K/AKT pathway [9].”
Recent developments in the treatment of Parkinson's Disease
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“The safety of NLY01 in humans is currently being tested in a clinical trial for PD. NLY01 belongs to the GLP-1R class of therapeutic agonists that have been used in the clinic for over 15 years.”
InfluentialDiet in Parkinson’s Disease: Critical Role for the Microbiome
Jackson, A., Forsyth, C. B., Shaikh, M., Voigt, R. M., Engen, P. A., Ramirez, V., & Keshavarzian, A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01245 · Cited by 145
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“Emerging evidence from preclinical studies suggests that GLP-1 receptor agonists may provide neuroprotection in several neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease [69].”
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Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020
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“In relation to the clinical use of GLP-1R agonists for the treatment of PD, pharmacokinetic–pharmacodynamic correlations of each GLP-1R agonist, from relatively short acting exenatide (in the form of Byetta [twice daily] and sustained release Bydureon [once weekly]) to longer acting dulaglutide, should be closely exam…”
MethodInfluentialIncretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., & Edison, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01792-4 · Cited by 136
“The involvement of GLP-1 in PD can be simplified to the activation of the MAPK/ extracellular signal-regulated kinase 1/2 (ERK) pathway, which has an important role in synaptic plasticity, and the PI3K/Akt pathway signaled by GLP-1 receptor stimulation and the subsequent increase in cAMP and PKA and PI3K activation [7…”
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“The GLP-1 and PI3K are demonstrated to be the keys behind the neuroprotective effect of Vilda in different disorders [5].”
BackgroundTanycytes control hypothalamic liraglutide uptake and its anti-obesity actions
Imbernon, M., Saponaro, C., Helms, H. C. C., Duquenne, M., Fernandois, D., Deligia, E., Denis, R. G. P., Chao, D. H. M., Rasika, S., Staels, B., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.06.002 · Cited by 124
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“GLP-1 could also promote the insulin secretion in the hyperglycemic state (Athauda and Foltynie 2016).”
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Self-citationGLP-1 receptor agonists effect on cognitive function in patients with and without type 2 diabetes
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Glucagon like peptide-1 (GLP-1) likes Alzheimer’s disease
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“The underlying mechanisms for GLP-1 receptors producing neuroprotection and antinociception are complicated and debatable (Athauda and Foltynie, 2016).”
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“Nevertheless, a single unifying mechanism of action underlying the neuroprotective properties of GLP-1RAs or putative disease modification remains a matter of investigation [4,17,22,38,51,83].”
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“GLP-1 is an incretin hormone with documented prominent neuroprotective action, providing protection against oxidative damage, apoptosis, inflammation and autophagy (Athauda and Foltynie, 2016; Sharma et al., 2014).”
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“GLP-1RAs are involved in mitochondrial function, enhancing the mitochondrial apoptotic pathway and reducing oxidative stress [469,470].”
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“GLP- 1 analogs with increased half- lives are being employed to combat T2DM as an adjunct to antidiabetic therapy (Athauda & Foltynie, 2016).”
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“GLP-1 increases insulin secretion from pancreatic ß cells and suppresses glucagon secretion from this organ’s α cells [156].”
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Suzuki, R., Brown, G. A., Christopher, J. A., Scully, C. C. G., & Congreve, M. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00835 · Cited by 64
Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson’s disease
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“Preliminary studies in PD cellular and animal models of neurodegeneration show efficacy in using these multi-agonists for enhanced brain function, including improvements over single GLP-1R agonism [5,19,26,33,43,44].”
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“Pre-clinical studies have demonstrated anti-PD effects of GLP-1R agonists and clinical trials are underway to evaluate the efficacy of GLP-1R agonists in slowing disease progression and alleviating symptoms in PD patients [10, 11].”
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“Hence, a treatment to improve insulin resistance may be useful for PD patients (Athauda and Foltynie, 2016).”
BackgroundPanagaki, T., Michael, M., & Hölscher, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-16488-x · Cited by 63
Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis
Geloneze, B., Júnior, J. C. D. L., & Velloso, L. A. (2017) · Drugs · doi:10.1007/s40265-017-0706-4 · Cited by 64
“The deceleration of gastric emptying is subject to rapid tachyphylaxis, which results in an attenuation of the effect on glycemic control after long-term use in humans [75] Control of ovarian cancer cells proliferation GLP-1RA inhibited growth of ovarian cancer cells through inhibition of the PI3K/Akt pathway [76] Inh…”
BackgroundGut microbiome: An intermediary to neurotoxicity
Dempsey, J. L., Little, M., & Cui, J. Y. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.08.005 · Cited by 63
“, 2018) with GLP-1 protecting against neurotoxicity of various etiologies (Athauda and Foltynie, 2016; Chang et al., 2018; Khalilnezhad and Taskiran, 2018).”
BackgroundRasha, R. Y., El-Yamany, M. F., Saad, M. A., & El-Sahar, A. E. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173612 · Cited by 59
Lin, K.-J., Wang, T., Chen, S., Lin, K.-L., Liou, C., Lan, M., Chuang, Y., Chuang, J., Wang, P., Lee, J., et al. (2021) · Antioxidants · doi:10.3390/antiox10121935 · Cited by 63
Drug Repurposing in Parkinson’s Disease
Athauda, D. S., & Foltynie, T. (2018) · CNS Drugs · doi:10.1007/s40263-018-0548-y · Cited by 59
Self-citationA Stage-Based Approach to Therapy in Parkinson’s Disease
Carrarini, C., Russo, M., Dono, F., Pietro, M. D., Rispoli, M. G., Stefano, V. D., Ferri, L., Barbone, F., Vitale, M., Thomas, A., et al. (2019) · Biomolecules · doi:10.3390/biom9080388 · Cited by 58
Yang, X., Qiang, Q., Li, N., Feng, P., Wei, W., & Hölscher, C. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.844697 · Cited by 58
Wu, H., Wei, J., Zhao, X., Liu, Y., Chen, Z., Wei, K., Lu, J., Chen, W., Jiang, M., Li, S., et al. (2022) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10351 · Cited by 59
“Accumulating evidence has revealed that both gut microbiota and microbial metabolites can affect the enteric nervous system (ENS) and the central nervous system (CNS) via the microbiota-gut-brain axis, suggesting intestinal dysbiosis might be closely associated with PD.11 Therefore, we used 16S rRNA sequencing combine…”
ResultInfluentialVentorp, F., Bay-Richter, C., Nagendra, A. S., Janelidze, S., Matsson, V. S., Lipton, J., Nordström, U., Westrin, Å., Brundin, P., & Brundin, L. (2017) · Journal of Parkinson’s Disease · doi:10.3233/jpd-171068 · Cited by 56
“Exendin-4 is also thought to exert anti-inflammatory effects in the central nervous system (CNS), such as suppress the production of the cytokines tumor necrosis factor- (TNF- ), interleukin-1 (IL-1 ) and the inducible nitric oxide synthase (iNOS) [8, 13] although the precise underlying mechanisms are not well charact…”
BackgroundSharma, N., Soni, R., Sharma, M., Chatterjee, S., Parihar, N., Mukarram, M., kale, R., Sayyed, A. A., Behera, S. K., & Khairnar, A. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03005-z · Cited by 54
Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy
Bu, L.-L., Liu, Y., Shen, Y., Fan, Y., Yu, W., Jiang, D., Tang, Y., Yang, Y., Wu, P., Zuo, C., et al. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01018-5 · Cited by 54
Seppa, K., Toots, M., Reimets, R., Jagomäe, T., Koppel, T., Pallase, M., Hasselholt, S., Krogsbaek, M., Nyengaard, J. R., Vasar, E., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-52295-2 · Cited by 54
Approaches to Disease Modification for Parkinson's Disease: Clinical Trials and Lessons Learned
Hung, A. Y., & Schwarzschild, M. A. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00964-w · Cited by 53
“Other neuroprotective mechanisms have also been proposed, including beneficial effects on mitochondrial function, synaptic plasticity, neurogenesis, and enhancing the actions of brain-derived neurotrophic factor [75].”
BackgroundBiological Membrane-Penetrating Peptides: Computational Prediction and Applications
de Oliveira, E. C. L., da Costa, K. S., Taube, P. S., Lima, A. H., & Sales, C. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.838259 · Cited by 60
“Some studies displayed that the administration of this peptide peripherally can cross the BBB in humans (Hunter and Hölscher, 2012; Athauda et al., 2017), besides exhibiting neuroprotective effects on several neurodegenerative models, mainly in PD (Athauda and Foltynie, 2016).”
BackgroundRocha‐Ferreira, E., Poupon-Bejuit, L., Zelco, A., Leverin, A., Nair, S., Jonsdotter, A., Carlsson, Y., Thornton, C., Hagberg, H., & Rahim, A. A. (2018) · Brain · doi:10.1093/brain/awy220 · Cited by 51
“This mechanism of action is thought to increase the anti- versus pro-apoptotic bcl-2 family protein balance (Brywe et al., 2005; Athauda and Foltynie, 2016), attenuate neuroinflammation and stabilize the blood–brain barrier post-transient middle cerebral artery occlusion in non- (Chen et al.”
BackgroundMousa, S. A., & Ayoub, B. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.249217 · Cited by 52
“Blood-brain barrier crossing studies are an interesting part of gliptins’ repurposing and are still a controversy (Chen et al., 2015), while GLP-1 crossed the blood-brain barrier in all reported investigations (Hunter and Holscher, 2012; Athauda and Foltynie, 2016).”
InfluentialBadawi, G. A., Fattah, M. A. A. E., Zaki, H. F., & Sayed, M. I. E. (2019) · Neurotoxicity Research · doi:10.1007/s12640-019-9998-3 · Cited by 53
Pang, J., Feng, J. N., Ling, W., & Jin, T. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.06.003 · Cited by 52
Fu, Z., Gong, L., Liu, J., Wu, J., Barrett, E. J., Aylor, K. W., & Liu, Z. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00555 · Cited by 52
Dementia in Diabetes: The Role of Hypoglycemia
Husain, K. H., Sarhan, S. F., AlKhalifa, H. K. A. A., Buhasan, A., Moin, A. S. M., & Butler, A. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129846 · Cited by 52
Neuroprotective Effects of Eexenatide in a Rotenone-Induced Rat Model of Parkinson’s Disease
Aksoy, D., Solmaz, V., Çavuşoğlu, T., Meral, A., Ateş, U., & Erbaş, O. (2017) · The American Journal of the Medical Sciences · doi:10.1016/j.amjms.2017.05.002 · Cited by 51
Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
Marchetti, B. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101664 · Cited by 52
“convert astrocytes into a neurotoxic A1 reactive subtype [346].”
Zhang, Y., Xu, S., Qian, Y., Mo, C., Ai, P., Yang, X., & Xiao, Q. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1099018 · Cited by 51
“GLP-1 from the intestine enters circulatory system through intestinal capillaries, and then crosses the blood–brain barrier to enter the brain tissue (Athauda and Foltynie, 2016), and exerts a physiological role by binding to GLP-1R, which is widely expressed in neurons, astrocytes, and microglia (Hölscher, 2014; Kim…”
BackgroundAnimal Venom Peptides as a Treasure Trove for New Therapeutics Against Neurodegenerative Disorders
Yang, X., Wang, Y., Wu, C., & Ling, E. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666181031122438 · Cited by 49
Lin, T., Lin, K.-J., Lin, H., Lin, K.-L., Lan, M., Wang, P., Wang, T., Wang, F., Tsai, P.-C., Liou, C., et al. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.697440 · Cited by 50
“Repurposing of drugs has gained the interest of researchers recently and the neuroprotective effect of the T2DM drugs GLP-1RA on PD has been demonstrated across a range of experimental models of PD (Athauda and Foltynie, 2016).”
BackgroundIncretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury
Glotfelty, E. J., Delgado, T., Tovar‐y‐Romo, L. B., Luo, Y., Hoffer, B. J., Olson, L., Karlsson, T. E., Mattson, M. P., Harvey, B. K., Tweedie, D., et al. (2019) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00003 · Cited by 48
Niazi, S., Gnesin, F., Thein, A.-S., Andreasen, J. R., Horwitz, A., Mouhammad, Z. A., Jawad, B. N., Niazi, Z., Pourhadi, N., Zareini, B., et al. (2024) · Ophthalmology · doi:10.1016/j.ophtha.2024.03.004 · Cited by 47
Pirhaghi, M., Mamashli, F., Moosavi-Movahedi, F., Arghavani, P., Amiri, A., Davaeil, B., Mohammad-Zaheri, M., Mousavi-Jarrahi, Z., Sharma, D., Langel, Ü., et al. (2024) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.3c01167 · Cited by 47
Li, Y., Glotfelty, E. J., Karlsson, T. E., Fortuno, L. V., Harvey, B. K., & Greig, N. H. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15521 · Cited by 47
“…have efficacy in treating a variety of neurological disorders, including traumatic brain injury (Glotfelty et al., 2019; Greig et al., 2014), PD (Athauda & Foltynie, 2016; Glotfelty et al., 2020; Kim et al., 2017), AD (Hölscher, 2020), stroke (Chen et al., 2018; Li et al., 2009; Zhang et al.,…”
BackgroundTsai, W.-H., Sung, F., Chiu, L., Shih, Y., Tsai, M.-C., & Wu, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.765446 · Cited by 49
“On the other hand, GLP-1 RA crossed the BBB successfully (Hunter and Hölscher, 2012; Athauda and Foltynie, 2016).”
BackgroundGlucagon-like Peptide-1 (GLP-1) and neurotransmitters signaling in epilepsy: An insight review
Koshal, P., Jamwal, S., & Kumar, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.015 · Cited by 45
“It is reported that, activation of microglial cell leads to generation of proinflammatory cytokines such as tumour necrosis factor alpha (TNF-a) which is associated with dopaminergic neuronal loss, enhanced glutamate release and generation of acquired channelopathies (Athauda and Foltynie, 2016; Walker and Sills, 2012…”
BackgroundInfluentialThe Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing
Su, Y., Wang, P., & Weng, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052668 · Cited by 45
Foltynie, T., & Athauda, D. S. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.008 · Cited by 46
Self-citationHe, W., Wang, H., Zhao, C., Tian, X., Li, L., & Wang, H. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.29204 · Cited by 45
“A large number of studies have demonstrated the neuroprotective effects of GLP‐1 analogue on central nervous system diseases, including stroke, Parkinson’s disease, and Alzheimer’s disease (Athauda & Foltynie, 2016; Calsolaro & Edison, 2015; C. H. Lee et al., 2011).”
BackgroundMahmoud, A. M. A., Mantawy, E. M., Wahdan, S. A., Ammar, R. M., & El‐Demerdash, E. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114238 · Cited by 45
Metadata
- Authors
- Athauda, D., & Foltynie, T.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- Athauda, Dilan
- Venue
- Drug Discovery Today
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 21
- Issue
- 5
- Pages
- 802-818
- ISSN
- 1359-6446 (ISSN-L)
- OpenAlex
- W2270971263
- Cited by
- 383
- References
- 258
- Citations by year
- 2026: 38 · 2025: 51 · 2024: 53 · 2023: 31 · 2022: 46 · 2021: 34 · 2020: 42 · 2019: 32 · 2018: 29 · 2017: 19 · 2016: 8
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Drug Discovery Today (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Michael J. Fox Foundation, Brain Research Trust, Cure Parkinson's Trust, Parkinson's UK
- European Commission (FP7)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- GLP-1 receptor, GLP-1 receptor agonists, Parkinson's disease, neuroprotection, exenatide, Parkinson's disease dementia, Alzheimer's disease, mechanism of action, therapeutic target
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Alzheimer Disease, Animals, Humans, Insulin Resistance, Learning, Mitochondria, Parkinson Disease, Signal Transduction, Proto-Oncogene Proteins c-akt, Glucagon-Like Peptide 1, Neurogenesis
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