{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:05:52Z","timestamp":1787583952748,"version":"build-2736575974"},"reference-count":203,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T00:00:00Z","timestamp":1641513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, and tremor. Considerable progress has been made to understand the exact mechanism leading to this disease. Most of what is known comes from the evidence of PD brains\u2019 autopsies showing a deposition of Lewy bodies\u2014containing a protein called \u03b1-synuclein (\u03b1-syn)\u2014as the pathological determinant of PD. \u03b1-syn predisposes neurons to neurotoxicity and cell death, while the other associated mechanisms are mitochondrial dysfunction and oxidative stress, which are underlying precursors to the death of dopaminergic neurons at the substantia nigra pars compacta leading to disease progression. Several mechanisms have been proposed to unravel the pathological cascade of these diseases; most of them share a particular similarity: cell-to-cell communication through exosomes (EXOs). EXOs are intracellular membrane-based vesicles with diverse compositions involved in biological and pathological processes, which their secretion is driven by the NLR family pyrin domain-containing three proteins (NLRP3) inflammasome. Toxic biological fibrils are transferred to recipient cells, and the disposal of damaged organelles through generating mitochondrial-derived vesicles are suggested mechanisms for developing PD. EXOs carry various biomarkers; thus, they are promising to diagnose different neurological disorders, including neurodegenerative diseases (NDDs). As nanovesicles, the applications of EXOs are not only restricted as diagnostics but also expanded to treat NDDs as therapeutic carriers and nano-scavengers. Herein, the aim is to highlight the potential incrimination of EXOs in the pathological cascade and progression of PD and their role as biomarkers and therapeutic carriers for diagnosing and treating this neuro-debilitating disorder.<\/jats:p>","DOI":"10.3390\/ph15010076","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:21:56Z","timestamp":1641759716000},"page":"76","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Exosomes in Parkinson: Revisiting Their Pathologic Role and Potential Applications"],"prefix":"10.3390","volume":"15","author":[{"given":"Yassamine","family":"Ouerdane","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Saad Dahlab University, Blida 09068, Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6516-8953","authenticated-orcid":false,"given":"Mohamed Y.","family":"Hassaballah","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdalrazeq","family":"Nagah","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9415-4267","authenticated-orcid":false,"given":"Tarek M.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hosny A. H.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Areej","family":"El-Baz","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-3420","authenticated-orcid":false,"given":"Mohamed S.","family":"Attia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/0277-9536(94)00138-J","article-title":"Neurodegenerative Diseases and Risk Factors: A Literature Review","volume":"40","author":"Emard","year":"1995","journal-title":"Soc. Sci. Med."},{"key":"ref_2","unstructured":"Ingenta Connect (2021, July 15). Current Limitations in the Treatment of Parkinson\u2019s and Alzheimer. Available online: https:\/\/www.ingentaconnect.com\/content\/ben\/cmc\/2018\/00000025\/00000041\/art00011."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"II19","DOI":"10.1007\/s00415-002-1204-4","article-title":"Treatment of Parkinson\u2019s Disease: Levodopa as the First Choice","volume":"249","author":"Katzenschlager","year":"2002","journal-title":"J. Neurol."},{"key":"ref_4","unstructured":"Gerlai, R.T. (2020). Chapter 23\u2014Parkinson\u2019s Disease. Behavioral and Neural Genetics of Zebrafish, Academic Press."},{"key":"ref_5","unstructured":"Sonne, J., Reddy, V., and Beato, M.R. (2021). Neuroanatomy, Substantia Nigra. StatPearls, StatPearls Publishing."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Veljkovic, E., Xia, W., Phillips, B., Wong, E.T., Ho, J., Oviedo, A., Hoeng, J., and Peitsch, M. (2018). Chapter 1\u2014Parkinson\u2019s Disease. Nicotine and Other Tobacco Compounds in Neurodegenerative and Psychiatric Diseases, Academic Press.","DOI":"10.1016\/B978-0-12-812922-7.00009-3"},{"key":"ref_7","unstructured":"Smelser, N.J., and Baltes, P.B. (2001). Dementia: Overview. International Encyclopedia of the Social & Behavioral Sciences, Pergamon."},{"key":"ref_8","unstructured":"Gandhi, K.R., and Saadabadi, A. (2021). Levodopa (L-Dopa). StatPearls, StatPearls Publishing."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00401-010-0711-0","article-title":"The Synaptic Pathology of \u03b1-Synuclein Aggregation in Dementia with Lewy Bodies, Parkinson\u2019s Disease and Parkinson\u2019s Disease Dementia","volume":"120","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bahbah, E.I., Ghozy, S., Attia, M.S., Negida, A., Emran, T.B., Mitra, S., Albadrani, G.M., Abdel-Daim, M.M., Uddin, M., and Simal-Gandara, J. (2021). Molecular Mechanisms of Astaxanthin as a Potential Neurotherapeutic Agent. Mar. Drugs, 19.","DOI":"10.3390\/md19040201"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6455","DOI":"10.1111\/j.1742-4658.2009.07344.x","article-title":"LRRK2 in Parkinson\u2019s Disease: Genetic and Clinical Studies from Patients","volume":"276","author":"Kumari","year":"2009","journal-title":"FEBS J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1750-1326-9-47","article-title":"The Role of the LRRK2 Gene in Parkinsonism","volume":"9","author":"Li","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Doyle, L.M., and Wang, M.Z. (2019). Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells, 8.","DOI":"10.3390\/cells8070727"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/jnc.15112","article-title":"Diagnostic and Therapeutic Potential of Exosomes in Alzheimer\u2019s Disease","volume":"156","author":"Martins","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_15","first-page":"182","article-title":"Extracellular Vesicles as Mediators of Neuron-Glia Communication","volume":"7","author":"Kuo","year":"2013","journal-title":"Front. Cell. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1002\/prca.200700522","article-title":"Oligodendrocytes Secrete Exosomes Containing Major Myelin and Stress-Protective Proteins: Trophic Support for Axons?","volume":"1","author":"Bretz","year":"2007","journal-title":"Proteom. Clin. Appl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12943-017-0706-8","article-title":"Role of Exosomal Proteins in Cancer Diagnosis","volume":"16","author":"Li","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"188497","DOI":"10.1016\/j.bbcan.2020.188497","article-title":"Power and Promise of Exosomes as Clinical Biomarkers and Therapeutic Vectors for Liquid Biopsy and Cancer Control","volume":"1875","author":"Ma","year":"2021","journal-title":"Biochim. Biophys. Acta (BBA)-Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113525","DOI":"10.1016\/j.expneurol.2020.113525","article-title":"From Inflammasome to Parkinson\u2019s Disease: Does the NLRP3 Inflammasome Facilitate Exosome Secretion and Exosomal Alpha-Synuclein Transmission in Parkinson\u2019s Disease?","volume":"336","author":"Si","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Grumezescu, A.M. (2016). Chapter 7\u2014Exosomes: Smart Nanospheres for Drug Delivery Naturally Produced by Stem Cells. Fabrication and Self-Assembly of Nanobiomaterials, William Andrew Publishing.","DOI":"10.1016\/B978-0-323-41533-0.00025-8"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ejpb.2020.07.026","article-title":"Exosomes as Drug Delivery Systems: A Brief Overview and Progress Update","volume":"154","author":"Patil","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7135","DOI":"10.33263\/BRIAC106.71357151","article-title":"Emerging Promise of Nanoparticle-Based Treatment for Parkinson\u2019s Disease","volume":"10","author":"Rahman","year":"2020","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0009-3084(93)90070-J","article-title":"Toxicity Screening of Liposomes","volume":"64","author":"Parnham","year":"1993","journal-title":"Chem. Phys. Lipids"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zieli\u0144ska, A., Carreir\u00f3, F., Oliveira, A.M., Neves, A., Pires, B., Venkatesh, D.N., Durazzo, A., Lucarini, M., Eder, P., and Silva, A.M. (2020). Polymeric Nanoparticles: Production, Characterization, Toxicology and Ecotoxicology. Molecules, 25.","DOI":"10.3390\/molecules25163731"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Antimisiaris, S.G., Mourtas, S., and Marazioti, A. (2018). Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery. Pharmaceutics, 10.","DOI":"10.20944\/preprints201810.0507.v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ijpharm.2017.02.010","article-title":"Asialoglycoprotein Receptor-Targeted Liposomes Loaded with a Norcantharimide Derivative for Hepatocyte-Selective Targeting","volume":"520","author":"Liu","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-019-0282-2","article-title":"Exosomes: Biogenesis, Biologic Function and Clinical Potential","volume":"9","author":"Zhang","year":"2019","journal-title":"Cell Biosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s10571-016-0366-z","article-title":"Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake","volume":"36","author":"Abels","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.apsb.2016.02.001","article-title":"Exosomes as Therapeutic Drug Carriers and Delivery Vehicles across Biological Membranes: Current Perspectives and Future Challenges","volume":"6","author":"Ha","year":"2016","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_30","first-page":"203","article-title":"Emerging Roles of Exosomes in Normal and Pathological Conditions: New Insights for Diagnosis and Therapeutic Applications","volume":"6","author":"Herschlik","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41392-020-00261-0","article-title":"Exosomes: Key Players in Cancer and Potential Therapeutic Strategy","volume":"5","author":"Dai","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.2147\/IJN.S291956","article-title":"A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes","volume":"16","author":"Gurunathan","year":"2021","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1194\/jlr.E086173","article-title":"Extracellular Vesicles: Lipids as Key Components of Their Biogenesis and Functions","volume":"59","author":"Record","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2164-14-319","article-title":"Characterization of Human Plasma-Derived Exosomal RNAs by Deep Sequencing","volume":"14","author":"Huang","year":"2013","journal-title":"BMC Genom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms1285","article-title":"Unidirectional Transfer of MicroRNA-Loaded Exosomes from T Cells to Antigen-Presenting Cells","volume":"2","author":"Mittelbrunn","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ncrna.2016.06.001","article-title":"Extracellular Vesicle Associated Long Non-Coding RNAs Functionally Enhance Cell Viability","volume":"1","author":"Hewson","year":"2016","journal-title":"Noncoding RNA Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12943-017-0663-2","article-title":"CircRNA: Functions and Properties of a Novel Potential Biomarker for Cancer","volume":"16","author":"Meng","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"789","DOI":"10.7150\/thno.18133","article-title":"Progress in Exosome Isolation Techniques","volume":"7","author":"Li","year":"2017","journal-title":"Theranostics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"29509","DOI":"10.3402\/jev.v4.29509","article-title":"High-Speed Centrifugation Induces Aggregation of Extracellular Vesicles","volume":"4","author":"Linares","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sidhom, K., Obi, P.O., and Saleem, A. (2020). A Review of Exosomal Isolation Methods: Is Size Exclusion Chromatography the Best Option?. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202007.0485.v2"},{"key":"ref_41","unstructured":"(2021, September 04). Exosomes in Parkinson Disease\u2014Journal of Neurochemistry\u2014Wiley Online Library. Available online: https:\/\/onlinelibrary.wiley.com\/doi\/full\/10.1111\/jnc.15288."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.nbd.2011.01.029","article-title":"Lysosomal Dysfunction Increases Exosome-Mediated Alpha-Synuclein Release and Transmission","volume":"42","author":"Seow","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature16531","article-title":"Structural Disorder of Monomeric \u03b1-Synuclein Persists in Mammalian Cells","volume":"530","author":"Theillet","year":"2016","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2012171118","DOI":"10.1073\/pnas.2012171118","article-title":"Structural Insights into \u03b1-Synuclein Monomer\u2013Fibril Interactions","volume":"118","author":"Kumari","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Vandendriessche, C., Bruggeman, A., Van Cauwenberghe, C., and Vandenbroucke, R.E. (2020). Extracellular Vesicles in Alzheimer\u2019s and Parkinson\u2019s Disease: Small Entities with Large Consequences. Cells, 9.","DOI":"10.3390\/cells9112485"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1093\/brain\/awaa090","article-title":"Microglial Exosomes Facilitate \u03b1-Synuclein Transmission in Parkinson\u2019s Disease","volume":"143","author":"Guo","year":"2020","journal-title":"Brain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s40478-019-0821-4","article-title":"Exosome Release and Neuropathology Induced by \u03b1-Synuclein: New Insights into Protective Mechanisms of Drp1 Inhibition","volume":"7","author":"Fan","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"13010","DOI":"10.1073\/pnas.0903691106","article-title":"Inclusion Formation and Neuronal Cell Death through Neuron-to-Neuron Transmission of \u03b1-Synuclein","volume":"106","author":"Desplats","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","unstructured":"(2021, September 04). Biological Properties of Extracellular Vesicles and Their Physiological Functions. Available online: https:\/\/www.tandfonline.com\/doi\/full\/10.3402\/jev.v4.27066."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018): A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.neulet.2013.06.009","article-title":"Exosomes of BV-2 Cells Induced by Alpha-Synuclein: Important Mediator of Neurodegeneration in PD","volume":"548","author":"Chang","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41419-019-1404-9","article-title":"Microglia as Modulators of Exosomal Alpha-Synuclein Transmission","volume":"10","author":"Xia","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1074\/jbc.M114.585703","article-title":"Acceleration of \u03b1-Synuclein Aggregation by Exosomes","volume":"290","author":"Grey","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6838","DOI":"10.1523\/JNEUROSCI.5699-09.2010","article-title":"Cell-Produced \u03b1-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival","volume":"30","author":"Emmanouilidou","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.4161\/auto.36436","article-title":"Autophagy Modulates SNCA\/\u03b1-Synuclein Release, Thereby Generating a Hostile Microenvironment","volume":"10","author":"Poehler","year":"2014","journal-title":"Autophagy"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e22","DOI":"10.1038\/emm.2013.45","article-title":"Autophagic failure promotes the exocytosis and intercellular transfer of \u03b1-synuclein","volume":"45","author":"Lee","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/S1474-4422(09)70062-6","article-title":"Neuroinflammation in Parkinson\u2019s Disease: A Target for Neuroprotection?","volume":"8","author":"Hirsch","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.nbd.2015.03.003","article-title":"Glia and Alpha-Synuclein in Neurodegeneration: A Complex Interaction","volume":"85","author":"Wenning","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fimmu.2020.00033","article-title":"Molecular Signatures of Neuroinflammation Induced by ASynuclein Aggregates in Microglial Cells","volume":"11","author":"Sarkar","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_60","first-page":"1045","article-title":"Parkinson\u2019s Disease","volume":"75","author":"Clarke","year":"2007","journal-title":"Am. Fam. Phys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.neulet.2017.02.045","article-title":"MicroRNA Biomarkers of Parkinson\u2019s Disease in Serum Exosome-like Microvesicles","volume":"644","author":"Cao","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_62","unstructured":"(2021, August 04). Parkinson\u2019s Disease\u2014Clinical Evidence Handbook\u2014American Family Physician. Available online: https:\/\/www.aafp.org\/afp\/2007\/0401\/p1045.html."},{"key":"ref_63","unstructured":"(2021, August 04). Biomarkers in Parkinson\u2019s Disease: An Update. Current Opinion in Neurology. Available online: https:\/\/journals.lww.com\/co-neurology\/Abstract\/2012\/08000\/Biomarkers_in_Parkinson_s_disease__an_update.12.aspx."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jconrel.2020.04.017","article-title":"Astrocyte-Derived Extracellular Vesicles: Neuroreparative Properties and Role in the Pathogenesis of Neurodegenerative Disorders","volume":"323","author":"Upadhya","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105094","DOI":"10.1016\/j.neuint.2021.105094","article-title":"Activated Microglia Facilitate the Transmission of \u03b1-Synuclein in Parkinson\u2019s Disease","volume":"148","author":"Zheng","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Picca, A., Guerra, F., Calvani, R., Bucci, C., Lo Monaco, M.R., Bentivoglio, A.R., Landi, F., Bernabei, R., and Marzetti, E. (2019). Mitochondrial-Derived Vesicles as Candidate Biomarkers in Parkinson\u2019s Disease: Rationale, Design and Methods of the EXosomes in PArkiNson Disease (EXPAND) Study. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102373"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00401-014-1361-4","article-title":"Autophagy in Neuronal Cells: General Principles and Physiological and Pathological Functions","volume":"129","author":"Damme","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1600-0854.2007.00677.x","article-title":"Induction of Autophagy Promotes Fusion of Multivesicular Bodies with Autophagic Vacuoles in K562 Cells","volume":"9","author":"Fader","year":"2008","journal-title":"Traffic"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3389\/fimmu.2014.00403","article-title":"Exosomes and Autophagy: Coordinated Mechanisms for the Maintenance of Cellular Fitness","volume":"5","author":"Baixauli","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/81834","article-title":"Chronic Systemic Pesticide Exposure Reproduces Features of Parkinson\u2019s Disease","volume":"3","author":"Betarbet","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.neuroscience.2014.11.004","article-title":"Rotenone Impairs Autophagic Flux and Lysosomal Functions in Parkinson\u2019s Disease","volume":"284","author":"Wu","year":"2015","journal-title":"Neuroscience"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/srep00898","article-title":"Environmental Toxins Trigger PD-like Progression via Increased Alpha-Synuclein Release from Enteric Neurons in Mice","volume":"2","author":"Schwarz","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Vella, L.J., Hill, A.F., and Cheng, L. (2016). Focus on Extracellular Vesicles: Exosomes and Their Role in Protein Trafficking and Biomarker Potential in Alzheimer\u2019s and Parkinson\u2019s Disease. Int. J. Mol. Sci., 17, Available online: https:\/\/www.mdpi.com\/1422-0067\/17\/2\/173\/htm.","DOI":"10.3390\/ijms17020173"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1126\/science.1140481","article-title":"A MicroRNA Feedback Circuit in Midbrain Dopamine Neurons","volume":"317","author":"Kim","year":"2007","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jconrel.2019.10.007","article-title":"MicroRNA Delivery through Nanoparticles","volume":"313","author":"Lee","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/jnc.14645","article-title":"Japanese Encephalitis Virus Infected Microglial Cells Secrete Exosomes Containing Let-7a\/b That Facilitate Neuronal Damage via Caspase Activation","volume":"149","author":"Mukherjee","year":"2018","journal-title":"J Neurochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1096\/fj.201700673r","article-title":"Increased MiR-124-3p in Microglial Exosomes Following Traumatic Brain Injury Inhibits Neuronal Inflammation and Contributes to Neurite Outgrowth via Their Transfer into Neurons","volume":"32","author":"Huang","year":"2018","journal-title":"FASEB J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e17478","DOI":"10.1097\/MD.0000000000017478","article-title":"Differential Proteomic Analysis of Serum Exosomes Reveals Alterations in Progression of Parkinson Disease","volume":"98","author":"Jiang","year":"2019","journal-title":"Medicine"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular Vesicles: Exosomes, Microvesicles, and Friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3389\/fncel.2014.00156","article-title":"Identification of Circulating MicroRNAs for the Differential Diagnosis of Parkinson\u2019s Disease and Multiple System Atrophy","volume":"8","author":"Vallelunga","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/jnr.23377","article-title":"Identification of Blood Serum Micro-RNAs Associated with Idiopathic and LRRK2 Parkinson\u2019s Disease","volume":"92","author":"Compta","year":"2014","journal-title":"J. Neurosci. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.parkreldis.2015.11.014","article-title":"Identification of a Panel of Five Serum MiRNAs as a Biomarker for Parkinson\u2019s Disease","volume":"22","author":"Ding","year":"2016","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3233\/JPD-012144","article-title":"Plasma-Based Circulating MicroRNA Biomarkers for Parkinson\u2019s Disease","volume":"2","author":"Khoo","year":"2012","journal-title":"J. Parkinson\u2019s Dis."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Burgos, K., Malenica, I., Metpally, R., Courtright, A., Rakela, B., Beach, T., Shill, H., Adler, C., Sabbagh, M., and Villa, S. (2014). Profiles of Extracellular MiRNA in Cerebrospinal Fluid and Serum from Patients with Alzheimer\u2019s and Parkinson\u2019s Diseases Correlate with Disease Status and Features of Pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094839"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1007\/s00415-013-6900-8","article-title":"Profile of MicroRNAs in the Plasma of Parkinson\u2019s Disease Patients and Healthy Controls","volume":"260","author":"Cardo","year":"2013","journal-title":"J. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"37043","DOI":"10.18632\/oncotarget.6158","article-title":"Altered MicroRNA Profiles in Cerebrospinal Fluid Exosome in Parkinson Disease and Alzheimer Disease","volume":"6","author":"Gui","year":"2015","journal-title":"Oncotarget"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.nbd.2014.08.003","article-title":"MicroRNAs as Modulators and Biomarkers of Inflammatory and Neuropathic Pain Conditions","volume":"71","author":"Andersen","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s00401-014-1314-y","article-title":"Plasma Exosomal \u03b1-Synuclein Is Likely CNS-Derived and Increased in Parkinson\u2019s Disease","volume":"128","author":"Shi","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1002\/mds.26686","article-title":"Ser(P)-1292 LRRK2 in Urinary Exosomes Is Elevated in Idiopathic Parkinson\u2019s Disease","volume":"31","author":"Fraser","year":"2016","journal-title":"Mov. Disord."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Figura, M., Sitkiewicz, E., \u015awiderska, B., Milanowski, \u0141., Szlufik, S., Koziorowski, D., and Friedman, A. (2021). Proteomic Profile of Saliva in Parkinson\u2019s Disease Patients: A Proof of Concept Study. Brain Sci., 11.","DOI":"10.3390\/brainsci11050661"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"38905","DOI":"10.1074\/jbc.M605798200","article-title":"S100A16, a Novel Calcium-Binding Protein of the EF-Hand Superfamily","volume":"281","author":"Sturchler","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_92","unstructured":"(2021, November 25). A Comprehensive Characterisation of the Salivary Proteome of Patients with Parkinson\u2019s Disease\u2014MDS Abstracts. Available online: https:\/\/www.mdsabstracts.org\/abstract\/a-comprehensive-characterisation-of-the-salivary-proteome-of-patients-with-parkinsons-disease\/."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Serrano, A., Apolloni, S., Rossi, S., Lattante, S., Sabatelli, M., Peric, M., Andjus, P., Michetti, F., Carr\u00ec, M.T., and Cozzolino, M. (2019). The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis. Cells, 8.","DOI":"10.3390\/cells8101261"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1089\/neu.2018.6170","article-title":"S100 Calcium-Binding Protein A9 Knockout Contributes to Neuroprotection and Functional Improvement after Traumatic Brain Injury","volume":"37","author":"Qiu","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0028-3843(14)60136-5","article-title":"Neuron-Specific Enolase and S 100B Protein as Predictors of Outcome in Ischaemic Stroke","volume":"44","author":"Tomasiuk","year":"2010","journal-title":"Neurol. Neurochir. Pol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41586-018-0237-5","article-title":"Nuclear Arp2\/3 Drives DNA Break Clustering for Homology-Directed Repair","volume":"559","author":"Schrank","year":"2018","journal-title":"Nature"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/ncb2502","article-title":"Syndecan-Syntenin-ALIX Regulates the Biogenesis of Exosomes","volume":"14","author":"Baietti","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"11795735211029114","DOI":"10.1177\/11795735211029114","article-title":"Salivary Heme Oxygenase-1: A Potential Biomarker for Central Neurodegeneration","volume":"13","author":"Galindez","year":"2021","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1073\/pnas.61.2.748","article-title":"The Enzymatic Conversion of Heme to Bilirubin by Microsomal Heme Oxygenase","volume":"61","author":"Tenhunen","year":"1968","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"298","DOI":"10.3389\/fncel.2014.00298","article-title":"An Association Study between Heme Oxygenase-1 Genetic Variants and Parkinson\u2019s Disease","volume":"8","author":"Ayuso","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1111\/jnc.15167","article-title":"Characterization and Heme Oxygenase-1 Content of Extracellular Vesicles in Human Biofluids","volume":"157","author":"Cressatti","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_102","first-page":"5278","article-title":"Circulating exosomal miRNAs as diagnostic biomarkers in Parkinson\u2019s disease","volume":"22","author":"Yao","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1093\/brain\/awv346","article-title":"Induction of \u03b1-Synuclein Aggregate Formation by CSF Exosomes from Patients with Parkinson\u2019s Disease and Dementia with Lewy Bodies","volume":"139","author":"Stuendl","year":"2016","journal-title":"Brain"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/mds.20243","article-title":"Levodopa in the Treatment of Parkinson\u2019s Disease: Current Controversies","volume":"19","author":"Olanow","year":"2004","journal-title":"Mov. Disord."},{"key":"ref_105","first-page":"1044","article-title":"Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease: A 4-Year Randomized Controlled Trial","volume":"61","author":"Holloway","year":"2004","journal-title":"Arch. Neurol."},{"key":"ref_106","unstructured":"PubMed (2021, November 25). A Five-Year Study of the Incidence of Dyskinesia in Patients with Early Parkinson\u2019s Disease Who Were Treated with Ropinirole or Levodopa, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/10816186\/."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2165\/00003495-199855001-00004","article-title":"Early Treatment of Parkinson\u2019s Disease with Cabergoline Delays the Onset of Motor Complications. Results of a Double-Blind Levodopa Controlled Trial. The PKDS009 Study Group","volume":"55","author":"Rinne","year":"1998","journal-title":"Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/mds.20724","article-title":"Pergolide versus Levodopa Monotherapy in Early Parkinson\u2019s Disease Patients: The PELMOPET Study","volume":"21","author":"Oertel","year":"2006","journal-title":"Mov. Disord."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1056\/NEJM197204062861421","article-title":"Post-Menopausal Bleeding after L-DOPA","volume":"286","author":"Wajsbort","year":"1972","journal-title":"N. Engl. J. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2165\/00003495-197204010-00004","article-title":"Antiparkinsonian Drugs: Pharmacological and Therapeutic Aspects","volume":"4","author":"Calm","year":"1972","journal-title":"Drugs"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1476-5381.1972.tb07249.x","article-title":"Action of l-\u03b1-Methyldopa-Hydrazine on the Blood Pressure of Patients Receiving Levodopa","volume":"44","author":"Calne","year":"1972","journal-title":"Br. J. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1136\/bmj.1.5791.53-d","article-title":"Gastritis and L-Dopa","volume":"1","author":"Riddoch","year":"1972","journal-title":"Br. Med. J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1212\/WNL.25.10.911","article-title":"Comparison of Dopa Decarboxylase Inhibitor (Carbidopa) Combined with Levodopa and Levodopa Alone in Parkinson\u2019s Disease","volume":"25","author":"Lieberman","year":"1975","journal-title":"Neurology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2165\/00003088-198713030-00002","article-title":"Clinical Pharmacokinetics of Anti-Parkinsonian Drugs","volume":"13","author":"Cedarbaum","year":"1987","journal-title":"Clin. Pharmacokinet."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/jps.2600690304","article-title":"Bioavailability of Marketed Levodopa Preparation in Dogs and Parkinsonian Patients","volume":"69","author":"Sasahara","year":"1980","journal-title":"J. Pharm. Sci."},{"key":"ref_116","first-page":"25","article-title":"Pharmacokinetics and Bioavailability of Sinemet CR: A Summary of Human Studies","volume":"39","author":"Yeh","year":"1989","journal-title":"Neurology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1212\/WNL.28.9.964","article-title":"Comparative Effectiveness of Two Extracerebral DOPA Decarboxylase Inhibitors in Parkinson Disease","volume":"28","author":"Lieberman","year":"1978","journal-title":"Neurology"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1002\/j.1552-4604.1997.tb04330.x","article-title":"Steady-state Pharmacokinetic Properties of Pramipexole in Healthy Volunteers","volume":"37","author":"Wright","year":"1997","journal-title":"J. Clin. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"439","DOI":"10.2165\/00002018-200326060-00005","article-title":"Comparison of the Risk of Adverse Events with Pramipexole and Ropinirole in Patients with Parkinson\u2019s Disease","volume":"26","author":"Etminan","year":"2003","journal-title":"Drug Saf."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2165\/00003088-200039040-00001","article-title":"Clinical Pharmacokinetics of Ropinirole","volume":"39","author":"Kaye","year":"2000","journal-title":"Clin. Pharmacokinet."},{"key":"ref_121","first-page":"273","article-title":"Side Effects of Ropinirole in Patients with Idiopathic Parkinson\u2019s Disease","volume":"109","author":"Titlic","year":"2008","journal-title":"Bratisl. Lek. Listy"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1002\/mds.25318","article-title":"Ropinirole Monotherapy Induced Severe Reversible Dyskinesias in Parkinson\u2019s Disease","volume":"28","author":"Batla","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"699","DOI":"10.2165\/11206750-000000000-00000","article-title":"Rotigotine Transdermal Patch","volume":"25","author":"Sanford","year":"2011","journal-title":"CNS Drugs"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"915","DOI":"10.2146\/ajhp050395","article-title":"Rasagiline: A Second-Generation Monoamine Oxidase Type-B Inhibitor for the Treatment of Parkinson\u2019s Disease","volume":"63","author":"Chen","year":"2006","journal-title":"Am. J. Health-Syst. Pharm."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1177\/0091270005277935","article-title":"Clinical Pharmacology of Rasagiline: A Novel, Second-generation Propargylamine for the Treatment of Parkinson Disease","volume":"45","author":"Chen","year":"2005","journal-title":"J. Clin. Pharmacol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1177\/0091270007304779","article-title":"Pharmacokinetics and Absolute Bioavailability of Selegiline Following Treatment of Healthy Subjects with the Selegiline Transdermal System (6 Mg\/24 h): A Comparison with Oral Selegiline Capsules","volume":"47","author":"Azzaro","year":"2007","journal-title":"J. Clin. Pharmacol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2165\/00002018-199819010-00002","article-title":"Safety of Selegiline (Deprenyl) in the Treatment of Parkinson\u2019s Disease","volume":"19","author":"Heinonen","year":"1998","journal-title":"Drug Saf."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s40263-017-0408-1","article-title":"Safinamide: A Review in Parkinson\u2019s Disease","volume":"31","author":"Blair","year":"2017","journal-title":"CNS Drugs"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s002280000244","article-title":"Pharmacokinetics of Entacapone, a Peripherally Acting Catechol-O-Methyltransferase Inhibitor, in Man","volume":"56","author":"Heikkinen","year":"2001","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.1212\/WNL.62.1_suppl_1.S39","article-title":"Safety and Tolerability of COMT Inhibitors","volume":"62","author":"Brooks","year":"2004","journal-title":"Neurology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/S0140-6736(05)61511-5","article-title":"Tolcapone and Fulminant Hepatitis","volume":"352","author":"Assal","year":"1998","journal-title":"Lancet"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"743","DOI":"10.2165\/00002018-200326110-00001","article-title":"Tolcapone-Related Liver Dysfunction","volume":"26","author":"Borges","year":"2003","journal-title":"Drug Saf."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/0009-9236(95)90035-7","article-title":"Integrated Pharmacokinetics and Pharmacodynamics of the Novel Catechol-O-methyltransferase Inhibitor Tolcapone during First Administration to Humans","volume":"57","author":"Dingemanse","year":"1995","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1007\/s40265-016-0623-y","article-title":"Opicapone: A Review in Parkinson\u2019s Disease","volume":"76","author":"Scott","year":"2016","journal-title":"Drugs"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s40262-012-0024-7","article-title":"Pharmacokinetics, Pharmacodynamics and Tolerability of Opicapone, a Novel Catechol-O-Methyltransferase Inhibitor, in Healthy Subjects","volume":"52","author":"Almeida","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2165\/00003088-198814010-00003","article-title":"Clinical Pharmacokinetics of Amantadine Hydrochloride","volume":"14","author":"Aoki","year":"1988","journal-title":"Clin. Pharmacokinet."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.2042-3306.1997.tb01650.x","article-title":"Amantadine and Equine Influenza: Pharmacology, Pharmacokinetics and Neurological Effects in the Horse","volume":"29","author":"Rees","year":"1997","journal-title":"Equine Vet. J."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/cpt1979266729","article-title":"Amantadine Kinetics in Healthy Young Subjects after Long-term Dosing","volume":"26","author":"Aoki","year":"1979","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/14656566.2018.1543407","article-title":"Chemical Management of Levodopa-Induced Dyskinesia in Parkinson\u2019s Disease Patients","volume":"20","year":"2019","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1590\/0004-282x20180140","article-title":"Apomorphine in the Treatment of Parkinson\u2019s Disease: A Review","volume":"76","author":"Pessoa","year":"2018","journal-title":"Arq. Neuro-Psiquiatr."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF00635711","article-title":"Pharmacokinetics and Pharmacodynamics of Procyclidine in Man","volume":"28","author":"Whiteman","year":"1985","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"815","DOI":"10.3163\/1536-5050.100.1.018","article-title":"Martindale: The Complete Drug Reference","volume":"100","author":"Wisher","year":"2012","journal-title":"J. Med. Libr. Assoc."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.ijporl.2015.03.027","article-title":"Acute Colonic Pseudo-Obstruction in a Child Taking Trihexyphenidyl for Drooling: Prescribers Beware","volume":"79","author":"Begbie","year":"2015","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Parkinson Study Group (2000). Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease: A Randomized Controlled Trial. Parkinson Study Group. JAMA, 284, 1931\u20131938.","DOI":"10.1001\/jama.284.15.1931"},{"key":"ref_145","unstructured":"PubMed (2021, November 25). Toxicity of 6-Hydroxydopamine and Dopamine for Dopaminergic Neurons in Culture, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/1977925\/."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/0014-5793(94)01056-0","article-title":"Intense Oxidative DNA Damage Promoted by L-Dopa and Its Metabolites. Implications for Neurodegenerative Disease","volume":"353","author":"Spencer","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/mds.870070105","article-title":"Neurotoxicity of Levodopa on Catecholamine-Rich Neurons","volume":"7","author":"Mena","year":"1992","journal-title":"Mov. Disord."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"S184","DOI":"10.1212\/WNL.47.6_Suppl_3.184S","article-title":"Is Levodopa Toxic?","volume":"47","author":"Fahn","year":"1996","journal-title":"Neurology"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S1353-8020(01)00023-2","article-title":"Levodopa Prolongs Life Expectancy and Is Non-Toxic to Substantia Nigra","volume":"8","author":"Rajput","year":"2001","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0733-8619(18)30213-5","article-title":"The Natural History of Parkinson\u2019s Disease in the Pre-Levodopa and Post-Levodopa Eras","volume":"10","author":"Hoehn","year":"1992","journal-title":"Neurol. Clin."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s007020050159","article-title":"Exogenous Levodopa Is Not Toxic to Elderly Subjects with Non-Parkinsonian Movement Disorders: Further Clinical Evidence","volume":"106","author":"Hagenah","year":"1999","journal-title":"J. Neural Transm."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1007\/s40263-020-00769-7","article-title":"Improving the Delivery of Levodopa in Parkinson\u2019s Disease: A Review of Approved and Emerging Therapies","volume":"34","author":"Urso","year":"2020","journal-title":"CNS Drugs"},{"key":"ref_153","first-page":"229","article-title":"Levodopa in the Treatment of Parkinson\u2019s Disease: An Old Drug Still Going Strong","volume":"5","author":"Poewe","year":"2010","journal-title":"Clin. Interv. Aging"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/bs.irn.2017.02.016","article-title":"The Nonmotor Features of Parkinson\u2019s Disease","volume":"132","author":"Titova","year":"2017","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_155","unstructured":"(2016). Non-Oral Dopaminergic Therapies for Parkinson\u2019s Disease: Current Treatments and the Future. NPJ Parkinson\u2019s Dis., 2, 1\u20137. Available online: https:\/\/www.nature.com\/articles\/npjparkd201623."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"(2021, November 25). Gut Dysfunction in Parkinson\u2019s Disease. Available online: https:\/\/www.wjgnet.com\/1007-9327\/full\/v22\/i25\/5742.htm.","DOI":"10.3748\/wjg.v22.i25.5742"},{"key":"ref_157","unstructured":"Chaudhuri, K.R., Qamar, M.A., Rajah, T., Loehrer, P., Sauerbier, A., Odin, P., and Jenner, P. (2021, November 25). Pharmacokinetics of Levodopa: Clinical Neuropharmacology. Available online: https:\/\/journals.lww.com\/clinicalneuropharm\/Citation\/1984\/03000\/Pharmacokinetics_of_Levodopa.2.aspx."},{"key":"ref_158","unstructured":"(2021, November 25). Eradication of Helicobacter pylori Infection Improves Levodopa Action, Clinical Symptoms and Quality of Life in Patients with Parkinson\u2019s Disease. Available online: https:\/\/journals.plos.org\/plosone\/article?id=10.1371\/journal.pone.0112330."},{"key":"ref_159","first-page":"S24","article-title":"Issues Important for Rational COMT Inhibition","volume":"55","author":"Dingemanse","year":"2000","journal-title":"Neurology"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1038\/jcbfm.2012.126","article-title":"Drug Transport across the Blood\u2013Brain Barrier","volume":"32","author":"Pardridge","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s10545-013-9608-0","article-title":"Blood\u2013Brain Barrier Structure and Function and the Challenges for CNS Drug Delivery","volume":"36","author":"Abbott","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"101694","DOI":"10.1016\/j.pneurobio.2019.101694","article-title":"Exosomal MiRNAs in Central Nervous System Diseases: Biomarkers, Pathological Mediators, Protective Factors and Therapeutic Agents","volume":"183","author":"Xia","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jconrel.2015.03.033","article-title":"Exosomes as Drug Delivery Vehicles for Parkinson\u2019s Disease Therapy","volume":"207","author":"Haney","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nbt.1807","article-title":"Delivery of SiRNA to the Mouse Brain by Systemic Injection of Targeted Exosomes","volume":"29","author":"Seow","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"eaba3967","DOI":"10.1126\/sciadv.aba3967","article-title":"Targeted Exosome Coating Gene-Chem Nanocomplex as \u201cNanoscavenger\u201d for Clearing \u03b1-Synuclein and Immune Activation of Parkinson\u2019s Disease","volume":"6","author":"Liu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.omtn.2021.01.022","article-title":"Exosomes Derived from MiR-188-3p-Modified Adipose-Derived Mesenchymal Stem Cells Protect Parkinson\u2019s Disease","volume":"23","author":"Li","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1002\/mds.25978","article-title":"Systemic Exosomal SiRNA Delivery Reduced Alpha-Synuclein Aggregates in Brains of Transgenic Mice","volume":"29","author":"Cooper","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/j.ymthe.2019.08.010","article-title":"Systemic Exosomal Delivery of ShRNA Minicircles Prevents Parkinsonian Pathology","volume":"27","author":"Izco","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jconrel.2018.08.035","article-title":"Dopamine-Loaded Blood Exosomes Targeted to Brain for Better Treatment of Parkinson\u2019s Disease","volume":"287","author":"Qu","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.omtn.2019.07.008","article-title":"Exosomal DNA Aptamer Targeting \u03b1-Synuclein Aggregates Reduced Neuropathological Deficits in a Mouse Parkinson\u2019s Disease Model","volume":"17","author":"Ren","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Haney, M.J., Gupta, R., Bohnsack, J.P., He, Z., Kabanov, A.V., and Batrakova, E.V. (2014). GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson\u2019s Disease Mouse Model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106867"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"156","DOI":"10.4161\/cam.1.3.5114","article-title":"Cell to Cell Signalling via Exosomes Through EsRNA","volume":"1","author":"Lotvall","year":"2007","journal-title":"Cell Adhes. Migr."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.phrs.2016.02.002","article-title":"Exosomes as a Potential Novel Therapeutic Tools against Neurodegenerative Diseases","volume":"113","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Gangadaran, P., and Ahn, B.-C. (2020). Extracellular Vesicle- and Extracellular Vesicle Mimetics-Based Drug Delivery Systems: New Perspectives, Challenges, and Clinical Developments. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050442"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1021\/acs.molpharmaceut.0c00195","article-title":"Potential Therapeutic Applications and Developments of Exosomes in Parkinson\u2019s Disease","volume":"17","author":"Luo","year":"2020","journal-title":"Mol. Pharm."},{"key":"ref_176","first-page":"504","article-title":"Parkinson\u2019s Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis","volume":"40","author":"DeMaagd","year":"2015","journal-title":"Pharm. Ther."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Haddad, F., Sawalha, M., Khawaja, Y., Najjar, A., and Karaman, R. (2017). Dopamine and Levodopa Prodrugs for the Treatment of Parkinson\u2019s Disease. Molecules, 23.","DOI":"10.3390\/molecules23010040"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1089\/dna.2011.1546","article-title":"Protective Effects of L-Dopa and Carbidopa Combined Treatments on Human Catecholaminergic Cells","volume":"31","author":"Colamartino","year":"2012","journal-title":"DNA Cell Biol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1038\/srep02534","article-title":"Ligand Modified Nanoparticles Increases Cell Uptake, Alters Endocytosis and Elevates Glioma Distribution and Internalization","volume":"3","author":"Gao","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ejpb.2020.05.001","article-title":"Nose-to-Brain Drug Delivery System with Ligand\/Cell-Penetrating Peptide-Modified Polymeric Nano-Micelles for Intracerebral Gliomas","volume":"152","author":"Kanazawa","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1080\/03639045.2021.1988097","article-title":"An Updated Review of Mesoporous Carbon as Novel Drug Delivery System","volume":"47","author":"Attia","year":"2021","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"376","DOI":"10.2174\/1570159X14666151230124904","article-title":"Drug Delivery Systems for Imaging and Therapy of Parkinson\u2019s Disease","volume":"14","author":"Chalon","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.bcp.2011.02.011","article-title":"Exosomes as Intercellular Signalosomes and Pharmacological Effectors","volume":"81","author":"Record","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ccr.2014.03.007","article-title":"Cancer-Secreted MiR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis","volume":"25","author":"Zhou","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"10396","DOI":"10.1038\/s41598-017-11220-1","article-title":"Targeting Transferrin Receptors at the Blood-Brain Barrier Improves the Uptake of Immunoliposomes and Subsequent Cargo Transport into the Brain Parenchyma","volume":"7","author":"Johnsen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3233\/JPD-181525","article-title":"The Amphetamine Induced Rotation Test: A Re-Assessment of Its Use as a Tool to Monitor Motor Impairment and Functional Recovery in Rodent Models of Parkinson\u2019s Disease","volume":"9","author":"Dunnett","year":"2019","journal-title":"J. Parkinson\u2019s Dis."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"509","DOI":"10.2174\/1389450120666191112155654","article-title":"The Therapeutic Potential of Quercetin in Parkinson\u2019s Disease: Insights into Its Molecular and Cellular Regulation","volume":"21","author":"Tamtaji","year":"2020","journal-title":"Curr. Drug Targets"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1080\/10717544.2020.1762262","article-title":"Brain Delivery of Quercetin-Loaded Exosomes Improved Cognitive Function in AD Mice by Inhibiting Phosphorylated Tau-Mediated Neurofibrillary Tangles","volume":"27","author":"Qi","year":"2020","journal-title":"Drug Deliv."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0076-6879(90)86093-B","article-title":"Role of Free Radicals and Catalytic Metal Ions in Human Disease: An Overview","volume":"186","author":"Halliwell","year":"1990","journal-title":"Methods Enzymol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.mcna.2018.10.014","article-title":"Parkinson\u2019s Disease","volume":"103","author":"Reich","year":"2019","journal-title":"Med. Clin. N. Am."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"48","DOI":"10.59566\/IJBS.2017.13048","article-title":"Molecular Mechanisms and Biological Functions of SiRNA","volume":"13","author":"Dana","year":"2017","journal-title":"Int. J. Biomed. Sci. IJBS"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1750-1326-3-19","article-title":"In Vivo Silencing of Alpha-Synuclein Using Naked SiRNA","volume":"3","author":"Lewis","year":"2008","journal-title":"Mol. Neurodegener."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s10787-017-0402-8","article-title":"Curcumin Affords Neuroprotection and Inhibits \u03b1-Synuclein Aggregation in Lipopolysaccharide-Induced Parkinson\u2019s Disease Model","volume":"26","author":"Sharma","year":"2018","journal-title":"Inflammopharmacology"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1172\/JCI64502","article-title":"ShRNA Targeting \u03b1-Synuclein Prevents Neurodegeneration in a Parkinson\u2019s Disease Model","volume":"125","author":"Zharikov","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2174\/1566523218666180430121323","article-title":"MiR-7 Replacement Therapy in Parkinson\u2019s Disease","volume":"18","year":"2018","journal-title":"Curr. Gene Ther."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1021\/acschemneuro.1c00076","article-title":"MiR-30a-5p Regulates GLT-1 Function via a PKC\u03b1-Mediated Ubiquitin Degradation Pathway in a Mouse Model of Parkinson\u2019s Disease","volume":"12","author":"Meng","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_197","doi-asserted-by":"crossref","unstructured":"Mosquera-Heredia, M.I., Morales, L.C., Vidal, O.M., Barcel\u00f3, E., Silvera-Redondo, C., V\u00e9lez, J.I., and Garavito-Galofre, P. (2021). Exosomes: Potential Disease Biomarkers and New Therapeutic Targets. Biomedicines, 9.","DOI":"10.3390\/biomedicines9081061"},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Soliman, H.M., Ghonaim, G.A., Gharib, S.M., Chopra, H., Farag, A.K., Hassanin, M.H., Nagah, A., Emad-Eldin, M., Hashem, N.E., and Yahya, G. (2021). Exosomes in Alzheimer\u2019s Disease: From Being Pathological Players to Potential Diagnostics and Therapeutics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910794"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.4103\/1673-5374.313026","article-title":"Potential Effects of Mesenchymal Stem Cell Derived Extracellular Vesicles and Exosomal MiRNAs in Neurological Disorders","volume":"16","author":"Nakano","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_200","doi-asserted-by":"crossref","unstructured":"Benmelouka, A.Y., Munir, M., Sayed, A., Attia, M.S., Ali, M.M., Negida, A., Alghamdi, B.S., Kamal, M.A., Barreto, G.E., and Ashraf, G.M. (2021). Neural Stem Cell-Based Therapies and Glioblastoma Management: Current Evidence and Clinical Challenges. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052258"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fcell.2020.00086","article-title":"Potential Roles of Exosomes in Parkinson\u2019s Disease: From Pathogenesis, Diagnosis, and Treatment to Prognosis","volume":"8","author":"Yu","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/acn3.175","article-title":"Identification of Distinct Circulating Exosomes in Parkinson\u2019s Disease","volume":"2","author":"Tomlinson","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/sctm.19-0174","article-title":"Exosomal 2\u2032,3\u2032-CNP from Mesenchymal Stem Cells Promotes Hippocampus CA1 Neurogenesis\/Neuritogenesis and Contributes to Rescue of Cognition\/Learning Deficiencies of Damaged Brain","volume":"9","author":"Chen","year":"2020","journal-title":"Stem Cells Transl. Med."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/1\/76\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:01:37Z","timestamp":1760364097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/1\/76"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,7]]},"references-count":203,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ph15010076"],"URL":"https:\/\/doi.org\/10.3390\/ph15010076","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,7]]}}}