{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T04:48:24Z","timestamp":1767847704433,"version":"3.49.0"},"reference-count":47,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004008","name":"Istituto Superiore di Sanit\u00e0","doi-asserted-by":"publisher","award":["Ricerca Corrente"],"award-info":[{"award-number":["Ricerca Corrente"]}],"id":[{"id":"10.13039\/501100004008","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004008","name":"Istituto Superiore di Sanit\u00e0","doi-asserted-by":"publisher","award":["ISS20-5cf22604a04d"],"award-info":[{"award-number":["ISS20-5cf22604a04d"]}],"id":[{"id":"10.13039\/501100004008","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.<\/jats:p>","DOI":"10.3390\/ijms23073456","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T14:55:35Z","timestamp":1647960935000},"page":"3456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study"],"prefix":"10.3390","volume":"23","author":[{"given":"Rita","family":"Pepponi","sequence":"first","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"De Simone","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"De Nuccio","sequence":"additional","affiliation":[{"name":"Research Coordination and Support Service, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Visentin","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Matteucci","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6590-7530","authenticated-orcid":false,"given":"Antonietta","family":"Bernardo","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrizia","family":"Popoli","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Ferrante","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13023-018-0785-7","article-title":"Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C","volume":"13","author":"Geberhiwot","year":"2018","journal-title":"Orphanet J. Rare Dis"},{"key":"ref_2","first-page":"100344","article-title":"Prevalence of Lysosomal Storage Disorders in Australia from 2009 to 2020","volume":"19","author":"Chin","year":"2022","journal-title":"Lancet Reg. Health West Pac."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s10545-014-9794-4","article-title":"Complex Lipid Trafficking in Niemann-Pick Disease Type C","volume":"38","author":"Vanier","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.bbalip.2019.04.002","article-title":"The Complexity of a Monogenic Neurodegenerative Disease: More than Two Decades of Therapeutic Driven Research into Niemann-Pick Type C Disease","volume":"1864","author":"Hammond","year":"2019","journal-title":"Biochim. Biophys. Acta\u2014Mol. Cell Biol. Lipids"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.3174\/ajnr.A3356","article-title":"Subcortical Volumetric Reductions in Adult Niemann-Pick Disease Type C: A Cross-Sectional Study","volume":"34","author":"Walterfang","year":"2013","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick Disease Type C","volume":"5","author":"Vanier","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s13023-018-0844-0","article-title":"Miglustat in Niemann-Pick Disease Type C Patients: A Review","volume":"13","author":"Pineda","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Br\u00e4uer, A.U., Kuhla, A., Holzmann, C., Wree, A., and Witt, M. (2019). Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann-Pick Disease Type C1. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184392"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1016\/j.bbamem.2010.12.001","article-title":"Adenosine Receptors and Brain Diseases: Neuroprotection and Neurodegeneration","volume":"1808","author":"Gomes","year":"2011","journal-title":"Biochim. Biophys. Acta\u2014Biomembr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1046\/j.1471-4159.2001.00607.x","article-title":"Adenosine in the Central Nervous System: Release Mechanisms and Extracellular Concentrations","volume":"79","author":"Latini","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"948","DOI":"10.2174\/156802611795347582","article-title":"Molecular Biology of Nucleoside Transporters and Their Distributions and Functions in the Brain","volume":"11","author":"Parkinson","year":"2011","journal-title":"CTMC"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1152\/physrev.00043.2006","article-title":"Physiology and Pathophysiology of Purinergic Neurotransmission","volume":"87","author":"Burnstock","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s11302-012-9309-4","article-title":"Cellular Function and Molecular Structure of Ecto-Nucleotidases","volume":"8","author":"Zimmermann","year":"2012","journal-title":"Purinergic Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pr.110.003285","article-title":"International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors\u2014An Update","volume":"63","author":"Fredholm","year":"2011","journal-title":"Pharm. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8936","DOI":"10.1007\/s12035-018-1030-z","article-title":"Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP\/PS1 Mouse Model of Alzheimer\u2019s Disease","volume":"55","author":"Lee","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_16","first-page":"467","article-title":"Targeting ENT1 and Adenosine Tone for the Treatment of Huntington\u2019s Disease","volume":"26","author":"Kao","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/hipo.20741","article-title":"Decreased Purinergic Inhibition of Synaptic Activity in a Mouse Model of Niemann-Pick Disease Type C","volume":"21","author":"Zhou","year":"2011","journal-title":"Hippocampus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15388","DOI":"10.1523\/JNEUROSCI.0558-13.2013","article-title":"The Stimulation of Adenosine A2A Receptors Ameliorates the Pathological Phenotype of Fibroblasts from Niemann-Pick Type C Patients","volume":"33","author":"Visentin","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neuropharm.2015.11.022","article-title":"Stimulation of Adenosine A2A Receptors Reduces Intracellular Cholesterol Accumulation and Rescues Mitochondrial Abnormalities in Human Neural Cell Models of Niemann-Pick C1","volume":"103","author":"Ferrante","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9782","DOI":"10.1038\/s41598-019-46268-8","article-title":"Adenosine A2A Receptor Stimulation Restores Cell Functions and Differentiation in Niemann-Pick Type C-like Oligodendrocytes","volume":"9","author":"Bernardo","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2017.10.013","article-title":"The Adenosine A2A Receptor Agonist T1\u201311 Ameliorates Neurovisceral Symptoms and Extends the Lifespan of a Mouse Model of Niemann-Pick Type C Disease","volume":"110","author":"Ferrante","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.vph.2007.12.004","article-title":"Dipyridamole, Cerebrovascular Disease, and the Vasculature","volume":"48","author":"Chakrabarti","year":"2008","journal-title":"Vasc. Pharmacol."},{"key":"ref_23","first-page":"4228","article-title":"The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson\u2019s Disease","volume":"68","author":"Burbulla","year":"2012","journal-title":"JoVE"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1038\/s41467-019-09801-x","article-title":"Adenosine Receptor Agonism Protects against NETosis and Thrombosis in Antiphospholipid Syndrome","volume":"10","author":"Ali","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12929-021-00766-y","article-title":"Emerging Roles of Dysregulated Adenosine Homeostasis in Brain Disorders with a Specific Focus on Neurodegenerative Diseases","volume":"28","author":"Chang","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1074\/mcp.M114.045609","article-title":"Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis","volume":"14","author":"Rauniyar","year":"2015","journal-title":"Mol. Cell. Proteom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/bpa.12592","article-title":"Purine-Related Metabolites and Their Converting Enzymes Are Altered in Frontal, Parietal and Temporal Cortex at Early Stages of Alzheimer\u2019s Disease Pathology","volume":"28","author":"Albasanz","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neuropharm.2015.04.031","article-title":"Comorbidities in Neurology: Is Adenosine the Common Link?","volume":"97","author":"Boison","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"104570","DOI":"10.1016\/j.nbd.2019.104570","article-title":"Synaptic and Memory Dysfunction in a \u03b2-Amyloid Model of Early Alzheimer\u2019s Disease Depends on Increased Formation of ATP-Derived Extracellular Adenosine","volume":"132","author":"Lopes","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1182\/blood-2004-01-0145","article-title":"Characterization of Monocyte Tissue Factor Activity Induced by IgG Antiphospholipid Antibodies and Inhibition by Dilazep","volume":"104","author":"Zhou","year":"2004","journal-title":"Blood"},{"key":"ref_31","first-page":"2006","article-title":"Treatment of Catastrophic Antiphospholipid Syndrome with Defibrotide, a Proposed Vascular Endothelial Cell Modulator","volume":"29","author":"Erkan","year":"2002","journal-title":"J. Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"722","DOI":"10.3389\/fnins.2017.00722","article-title":"Pivotal Role of Adenosine Neurotransmission in Restless Legs Syndrome","volume":"11","author":"Quiroz","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00213-011-2315-3","article-title":"Dipyridamole Monotherapy in Schizophrenia: Pilot of a Novel Treatment Approach by Modulation of Purinergic Signaling","volume":"218","author":"Wonodi","year":"2011","journal-title":"Psychopharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.phrs.2014.05.008","article-title":"Classical and Pleiotropic Actions of Dipyridamole: Not Enough Light to Illuminate the Dark Tunnel?","volume":"87","author":"Balakumar","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/jnc.14937","article-title":"Adenosine Inhibits Human Astrocyte Proliferation Independently of Adenosine Receptor Activation","volume":"153","author":"Marcelino","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_36","first-page":"413","article-title":"Receptors for Purines and Pyrimidines","volume":"50","author":"Ralevic","year":"1998","journal-title":"Pharm. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.pneurobio.2007.07.005","article-title":"Aspects of the General Biology of Adenosine A2A Signaling","volume":"83","author":"Fredholm","year":"2007","journal-title":"Prog. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1097\/ALN.0b013e3181b060f2","article-title":"Adenosine: An Old Drug Newly Discovered","volume":"111","author":"Eltzschig","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"16775","DOI":"10.1016\/S0021-9258(18)66633-5","article-title":"Type C Niemann-Pick Disease. A Parallel Loss of Regulatory Responses in Both the Uptake and Esterification of Low Density Lipoprotein-Derived Cholesterol in Cultured Fibroblasts","volume":"261","author":"Pentchev","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1016\/S0021-9258(18)45483-X","article-title":"Low Density Lipoprotein (LDL)-Mediated Suppression of Cholesterol Synthesis and LDL Uptake Is Defective in Niemann-Pick Type C Fibroblasts","volume":"262","author":"Liscum","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/hep.20868","article-title":"Cholesterol Accumulation and Liver Cell Death in Mice with Niemann-Pick Type C Disease","volume":"42","author":"Beltroy","year":"2005","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1194\/jlr.M700555-JLR200","article-title":"The Niemann-Pick C1 Gene Is Downregulated by Feedback Inhibition of the SREBP Pathway in Human Fibroblasts","volume":"49","author":"Garver","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/jcb.21200","article-title":"Characterization of Liver Disease and Lipid Metabolism in the Niemann-Pick C1 Mouse","volume":"101","author":"Garver","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.bbamem.2019.01.001","article-title":"Membrane Cholesterol Depletion Reduces Downstream Signaling Activity of the Adenosine A2A Receptor","volume":"1861","author":"McGraw","year":"2019","journal-title":"Biochim. Biophys. Acta\u2014Biomembr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9276","DOI":"10.1074\/jbc.M706275200","article-title":"Restricted Collision Coupling of the A2A Receptor Revisited","volume":"283","author":"Charalambous","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chembiol.2020.10.003","article-title":"Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum","volume":"28","author":"Esquejo","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1186\/1742-2094-10-89","article-title":"Reduction of Microglial Activity in a Model of Multiple Sclerosis by Dipyridamole","volume":"10","author":"Sloka","year":"2013","journal-title":"J. Neuroinflamm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:41:12Z","timestamp":1760136072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,22]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23073456"],"URL":"https:\/\/doi.org\/10.3390\/ijms23073456","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,22]]}}}