{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:35:52Z","timestamp":1785242152552,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Skybio LLC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Levodopa is the gold standard symptomatic treatment for Parkinson\u2019s disease. Disease progression due to alpha-synuclein accumulation, brain inflammation, and the loss of dopamine neurons, as well as motor fluctuations, due to variations in levodopa plasma levels, remain a significant problem for Parkinson\u2019s patients. Developing a therapeutic option that can simultaneously reduce the neuropathology associated with alpha-synuclein aggregation, attenuate oxidative stress and inflammation, and overcome variations in levodopa plasma levels is an unmet need to treat Parkinson\u2019s disease. We determined the pharmacokinetics and pharmacodynamics of a small molecule, dubbed Pegasus, that conjugates dopamine with a nonantibiotic doxycycline derivative via a molecular linker. Mice harboring the human A53T mutation of alpha-synuclein or treated with MPTP were injected once daily with 50 mg\/kg Pegasus for 2 weeks and assessed for motor, behavioral, and cognitive effects, followed by biochemical and histochemical analysis. Pegasus is a poor brain penetrant but it was metabolized to stable dopamine and tetracycline derivatives, and abundant plasma and brain levels of these metabolites were detected. Pegasus reduced soluble and insoluble alpha-synuclein levels, protected dopamine-producing neurons, and reduced astrocytic activation in A53T mice. Mice treated with Pegasus exhibited motor improvement (6.5 h) and reduction in anxiety-like behavior. Rotarod and grip strength improved in MPTP-treated mice when mice were treated with Pegasus or levodopa. Pegasus may be a multi-modal therapeutic option that can deliver stable dopamine into the CNS and reduce misfolded alpha-synuclein, activate dopamine receptors, and attenuate variations in dopamine levels.<\/jats:p>","DOI":"10.3390\/ijms26094251","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:50:17Z","timestamp":1745992217000},"page":"4251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Small Molecule Enhances Stable Dopamine Delivery to the Brain in Models of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Xiaoguang","family":"Liu","sequence":"first","affiliation":[{"name":"Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaeline L.","family":"Hebron","sequence":"additional","affiliation":[{"name":"Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2012-7063","authenticated-orcid":false,"given":"Charbel","family":"Moussa","sequence":"additional","affiliation":[{"name":"Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","article-title":"\u03b1-Synuclein in filamentous inclusions of Lewy bodies from Parkinson\u2019s disease and dementia with lewy bodies","volume":"95","author":"Spillantini","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/35081564","article-title":"Alpha-synuclein and neurodegenerative diseases","volume":"2","author":"Goedert","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"661","DOI":"10.20344\/amp.11978","article-title":"Parkinson\u2019s Disease: Clinical Review and Update","volume":"32","author":"Cabreira","year":"2019","journal-title":"Acta Medica Port."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and Treatment of Parkinson Disease: A Review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/ncpneuro0222","article-title":"Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson\u2019s disease","volume":"2","author":"Olanow","year":"2006","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1021\/acschemneuro.4c00169","article-title":"Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson\u2019s Disease","volume":"15","author":"Ploper","year":"2024","journal-title":"ACS Chem. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","article-title":"The blood-brain barrier: Bottleneck in brain drug development","volume":"2","author":"Pardridge","year":"2005","journal-title":"NeuroRx"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41577-022-00684-6","article-title":"Inflammation and immune dysfunction in Parkinson disease","volume":"22","author":"Tansey","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Troncoso-Escudero, P., Parra, A., Nassif, M., and Vidal, R.L. (2018). Outside in: Unraveling the Role of Neuroinflammation in the Progression of Parkinson\u2019s Disease. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00860"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40035-015-0042-0","article-title":"Neuroinflammation in Parkinson\u2019s disease and its potential as therapeutic target","volume":"4","author":"Wang","year":"2015","journal-title":"Transl. Neurodegener."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Castillo-Rangel, C., Marin, G., Hern\u00e1ndez-Contreras, K.A., Vichi-Ram\u00edrez, M.M., Zarate-Calderon, C., Torres-Pineda, O., Diaz-Chiguer, D.L., Gonz\u00e1lez, D.D.l.M., Apo, E.G., and Teco-Cortes, J.A. (2023). Neuroinflammation in Parkinson\u2019s Disease: From Gene to Clinic: A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065792"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S580","DOI":"10.1002\/mds.22037","article-title":"Pharmacokinetics and pharmacodynamics of levodopa","volume":"23","author":"Nutt","year":"2008","journal-title":"Mov. Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/mds.26050","article-title":"Improving L-dopa therapy: The development of enzyme inhibitors","volume":"30","author":"Gershanik","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s00228-013-1602-9","article-title":"Effect of moderate liver impairment on the pharmacokinetics of opicapone","volume":"70","author":"Rocha","year":"2014","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_16","first-page":"749","article-title":"Treatment Patterns in Patients with Incident Parkinson\u2019s Disease in the United States","volume":"9","author":"Houghton","year":"2019","journal-title":"J. Park. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2147\/NDT.S1660","article-title":"Optimizing levodopa therapy for Parkinson\u2019s disease with levodopa\/carbidopa\/entacapone: Implications from a clinical and patient perspective","volume":"4","author":"Brooks","year":"2008","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1212\/WNL.0000000000012868","article-title":"Dopaminergic Therapy for Motor Symptoms in Early Parkinson Disease Practice Guideline Summary: A Report of the AAN Guideline Subcommittee","volume":"97","author":"Pringsheim","year":"2021","journal-title":"Neurology"},{"key":"ref_19","first-page":"527","article-title":"Dosing frequency and medication adherence in chronic disease","volume":"18","author":"Coleman","year":"2012","journal-title":"J. Manag. Care Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1159\/000118882","article-title":"Motor fluctuations in levodopa treatment: Clinical pharmacology","volume":"36","author":"Stocchi","year":"1996","journal-title":"Eur. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20258","DOI":"10.1038\/s41598-020-76927-0","article-title":"CMT-3 targets different alpha-synuclein aggregates mitigating their toxic and inflammogenic effects","volume":"10","author":"Ploper","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105229","DOI":"10.1016\/j.parkreldis.2022.105229","article-title":"Repositioning doxycycline for treating synucleinopathies: Evidence from a pre-clinical mouse model","volume":"106","author":"Artioli","year":"2023","journal-title":"Park. Relat. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pereira, M.d.S., Nascimento, G.C.D., Bortolanza, M., Michel, P.P., Raisman-Vozari, R., and Del Bel, E. (2022). Doxycycline attenuates l-DOPA-induced dyskinesia through an anti-inflammatory effect in a hemiparkinsonian mouse model. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1045465"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, J., Wang, F., Mai, D., and Qu, S. (2020). Molecular Mechanisms of Glutamate Toxicity in Parkinson\u2019s Disease. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.585584"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sechi, G.P., and Sechi, M.M. (2024). Small Molecules, alpha-Synuclein Pathology, and the Search for Effective Treatments in Parkinson\u2019s Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011198"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1002\/glia.23472","article-title":"Microglial glutamate release evoked by alpha-synuclein aggregates is prevented by dopamine","volume":"66","author":"Acuna","year":"2018","journal-title":"Glia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"222","DOI":"10.2174\/187152709788680689","article-title":"Neuroprotective effects of tetracyclines: Molecular targets, animal models and human disease","volume":"8","author":"Orsucci","year":"2009","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2174\/1874210600802010005","article-title":"A role for non-antimicrobial actions of tetracyclines in combating oxidative stress in periodontal and metabolic diseases: A literature review","volume":"2","author":"Soory","year":"2008","journal-title":"Open Dent. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14669","DOI":"10.1073\/pnas.251341998","article-title":"Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson\u2019s disease","volume":"98","author":"Du","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1124\/pr.56.3.1","article-title":"Catecholamine metabolism: A contemporary view with implications for physiology and medicine","volume":"56","author":"Eisenhofer","year":"2004","journal-title":"Pharmacol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8968","DOI":"10.1073\/pnas.132197599","article-title":"Human \u03b1-synuclein-harboring familial Parkinson\u2019s disease-linked Ala-53 \u2192 Thr mutation causes neurodegenerative disease with \u03b1-synuclein aggregation in transgenic mice","volume":"99","author":"Lee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1093\/hmg\/ddr091","article-title":"Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated A\u03b2 in AD models","volume":"20","author":"Khandelwal","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1002\/emmm.201302771","article-title":"Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance","volume":"5","author":"Lonskaya","year":"2013","journal-title":"EMBO Mol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:24:36Z","timestamp":1760030676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094251"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094251","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}