{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:29:31Z","timestamp":1772087371034,"version":"3.50.1"},"reference-count":109,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms (bradykinesia, rigidity, resting tremor) and a wide range of non-motor features. The core pathological process is degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to striatal dopamine deficiency, while additional neurotransmitter systems contribute to non-motor symptoms. PD is a common age-related disorder; global estimates for 2019 indicate that more than 8.5 million people were living with PD, and prevalence increases steeply with age. Current pharmacological therapy is mainly symptomatic and is centered on levodopa and other dopaminergic strategies, but treatment response can be limited by motor fluctuations, dyskinesia, and adverse effects. Therefore, formulation and delivery innovations (e.g., dispersible preparations, intestinal gel, and continuous infusion approaches) aim to stabilize drug exposure and improve convenience, especially in patients with swallowing difficulties or advanced disease. This review summarizes conventional drug classes and their dosage forms, highlights formulation-driven strategies to improve efficacy and tolerability, and outlines emerging pathways and targets being explored for future therapies.<\/jats:p>","DOI":"10.3390\/brainsci16020226","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T11:11:28Z","timestamp":1771240288000},"page":"226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Parkinson\u2019s Disease: Conventional Pharmacotherapy, Drug Delivery Innovations, and Emerging Therapeutic Targets"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1859-0646","authenticated-orcid":false,"given":"Deepika","family":"Raina","sequence":"first","affiliation":[{"name":"School of Pharmacy, Graphic Era Hill University, Dehradun 248002, Uttrakhand, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4929-9619","authenticated-orcid":false,"given":"Chirag","family":"Marwah","sequence":"additional","affiliation":[{"name":"Chikara College of Pharmacy, Chitkara University, Rajpura, Patiala 140401, Punjab, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1699-2561","authenticated-orcid":false,"given":"Siddharth","family":"Singh","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, School of Pharmaceuticals and Population Health Informatics, DIT University, Dehradun 248009, Uttrakhand, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4839-4454","authenticated-orcid":false,"given":"Ansab","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Louisiana State University Health Sciences Center, Neuroscience Center, School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"574","DOI":"10.2174\/1871527320666210903101841","article-title":"Neurodegenerative disorders and the current state, pathophysiology, and management of Parkinson\u2019s disease","volume":"21","author":"Rahul","year":"2022","journal-title":"CNS Neurol. Disord.-Drug Targets"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2174\/1389450122666210623115505","article-title":"Parkinson\u2019s Disease: A Current Perspectives on Parkinson\u2019s Disease and Key Bioactive Natural Compounds as Future Potential Drug Candidates","volume":"23","author":"Ali","year":"2022","journal-title":"Curr. Drug Targets"},{"key":"ref_3","first-page":"229","article-title":"Sleep disturbances in progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS)","volume":"57","author":"Alster","year":"2023","journal-title":"Neurol. Neurochir. Pol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/S1474-4422(20)30036-3","article-title":"Initiation of pharmacological therapy in Parkinson\u2019s disease: When, why, and how","volume":"19","author":"Clarke","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.cortex.2022.03.009","article-title":"Regional changes of brain structure during progression of idiopathic Parkinson\u2019s disease\u2013A longitudinal study using deformation based morphometry","volume":"151","author":"Pieperhoff","year":"2022","journal-title":"Cortex"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/nrd.2018.136","article-title":"Therapeutic strategies for Parkinson disease: Beyond dopaminergic drugs","volume":"17","author":"Charvin","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107026","DOI":"10.1016\/j.parkreldis.2024.107026","article-title":"Update: Protective and risk factors for Parkinson disease","volume":"125","author":"Grotewold","year":"2024","journal-title":"Park. Relat. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrneurol.2016.152","article-title":"Advances in markers of prodromal Parkinson disease","volume":"12","author":"Postuma","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pe\u00f1a-Zelayeta, L., Delgado-Minjares, K.M., Villegas-Rojas, M.M., Le\u00f3n-Arcia, K., Santiago-Balmaseda, A., Andrade-Guerrero, J., P\u00e9rez-Segura, I., Ortega-Robles, E., Soto-Rojas, L.O., and Arias-Carri\u00f3n, O. (2025). Redefining non-motor symptoms in Parkinson\u2019s disease. J. Pers. Med., 15.","DOI":"10.20944\/preprints202503.1395.v1"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yang, N., Liu, J., Sun, D., Ding, J., Sun, L., Qi, X., and Yan, W. (2025). Motor symptoms of Parkinson\u2019s disease: Critical markers for early AI-assisted diagnosis. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1602426"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ardila Jurado, E., Z\u00fcnd-Hofer, L., Brugger, F., Nicastro, N., Bhatia, K.P., and K\u00e4gi, G. (2025). The role of presynaptic dopaminergic imaging in acquired neurological conditions affecting basal ganglia: A systematic review. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1660747"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.4103\/aian.AIAN_194_18","article-title":"Vascular parkinsonism: A review on management updates","volume":"22","author":"Udagedara","year":"2019","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1007\/s00702-025-02960-w","article-title":"Vascular parkinsonism: An update","volume":"132","author":"Jellinger","year":"2025","journal-title":"J. Neural Transm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1097\/MS9.0000000000001142","article-title":"Parkinson\u2019s disease updates: Addressing the pathophysiology, risk factors, genetics, diagnosis, along with the medical and surgical treatment","volume":"85","author":"Prajjwal","year":"2023","journal-title":"Ann. Med. Surg."},{"key":"ref_15","unstructured":"World Health Organization (2026, January 04). Parkinson Disease. Fact Sheet. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/parkinson-disease."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41531-024-00779-y","article-title":"A systematic review and meta-analysis of the prevalence of Parkinson\u2019s disease in lower to upper-middle-income countries","volume":"10","author":"Pereira","year":"2024","journal-title":"npj Park. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/S1474-4422(16)30230-7","article-title":"The epidemiology of Parkinson\u2019s disease: Risk factors and prevention","volume":"15","author":"Ascherio","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1021\/acsomega.4c09114","article-title":"Evolving Landscape of Parkinson\u2019s Disease Research: Challenges and perspectives","volume":"10","author":"Tenchov","year":"2025","journal-title":"ACS Omega"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1001\/jama.2014.3654","article-title":"Pharmacological treatment of Parkinson disease: A review","volume":"311","author":"Connolly","year":"2014","journal-title":"J. Am. Med. Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.5958\/0974-360X.2020.00354.6","article-title":"Nanotechnology in Parkinson\u2019s Disease\u2014A Review","volume":"13","author":"Acharya","year":"2020","journal-title":"Res. J. Pharm. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S1474-4422(19)30287-X","article-title":"The genetic architecture of Parkinson\u2019s disease","volume":"19","author":"Blauwendraat","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/neup.12777","article-title":"Parkinson\u2019s disease and parkinsonism: Clinicopathological discrepancies on diagnosis in three patients","volume":"41","author":"Toyoshima","year":"2021","journal-title":"Neuropathology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Miguel-Puga, A., Villafuerte, G., Salas-Pacheco, J., and Arias-Carri\u00f3n, O. (2017). Therapeutic interventions for vascular parkinsonism: A systematic review and meta-analysis. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00481"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/ana.26852","article-title":"Gene\u2013environment interactions for Parkinson\u2019s disease","volume":"95","author":"Reynoso","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41531-023-00568-z","article-title":"Linking environmental risk factors with epigenetic mechanisms in Parkinson\u2019s disease","volume":"9","author":"Tsalenchuk","year":"2023","journal-title":"npj Park. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1001\/archneur.2008.65.6.nct70003","article-title":"Parkinson Study Group PRECEPT Investigators. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease","volume":"65","author":"Schwarzschild","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3934\/Neuroscience.2023017","article-title":"Depletion of dopamine in Parkinson\u2019s disease and relevant therapeutic options: A review of the literature","volume":"10","author":"Ramesh","year":"2023","journal-title":"AIMS Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"434","DOI":"10.2174\/0118715273325667241212041540","article-title":"Beyond dopamine: Novel therapeutic pathways for Parkinson\u2019s disease through receptor signaling","volume":"24","author":"Bhushan","year":"2025","journal-title":"CNS Neurol. Disord.-Drug Targets"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e19818","DOI":"10.7717\/peerj.19818","article-title":"The role of T cells in the treatment of Parkinson\u2019s disease","volume":"13","author":"Lin","year":"2025","journal-title":"PeerJ"},{"key":"ref_31","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_32","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_33","doi-asserted-by":"crossref","first-page":"107133","DOI":"10.1016\/j.ejps.2025.107133","article-title":"Targeting bacterial and human levodopa decarboxylases for improved drug treatment of Parkinson\u2019s disease: Discovery and characterization of new inhibitors","volume":"211","author":"Reunanen","year":"2025","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1111\/jnc.12038","article-title":"Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson\u2019s disease: Linking to Akt\/GSK 3\u03b2 signaling pathway","volume":"123","author":"Gong","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1073\/pnas.1217296110","article-title":"Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration","volume":"110","author":"Chen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1080\/14737175.2023.2176220","article-title":"Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach","volume":"23","author":"Lees","year":"2023","journal-title":"Expert Rev. Neurother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1159\/000488138","article-title":"Dysphagia causes symptom fluctuations after oral L-DOPA treatment in a patient with Parkinson disease","volume":"10","author":"Sato","year":"2018","journal-title":"Case Rep. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Cornil\u0103, A., Iurian, S., Tomu\u021b\u0103, I., and Porfire, A. (2022). Orally dispersible dosage forms for paediatric use: Current knowledge and development of nanostructure-based formulations. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14081621"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1007\/s00415-023-11615-3","article-title":"Levodopa\u2013carbidopa intestinal gel in advanced Parkinson\u2019s disease: Long-term results from COSMOS","volume":"270","author":"Fasano","year":"2023","journal-title":"J. Neurol."},{"key":"ref_40","first-page":"100148","article-title":"Levodopa-Carbidopa Intestinal Gel may improve treatment-resistant freezing of gait in Parkinson\u2019s disease","volume":"7","author":"Shackleford","year":"2022","journal-title":"Clin. Park. Relat. Disord."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S1474-4422(24)00052-8","article-title":"Safety and efficacy of continuous subcutaneous levodopa\u2013carbidopa infusion (ND0612) for Parkinson\u2019s disease with motor fluctuations (BouNDless): A phase 3, randomised, double-blind, double-dummy, multicentre trial","volume":"23","author":"Espay","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s11910-012-0282-7","article-title":"Urate in Parkinson\u2019s disease: More than a biomarker?","volume":"12","author":"Chen","year":"2012","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_43","first-page":"28","article-title":"Experiencia did\u00e1ctica del tema de hidrocarburos en la materia Qu\u00edmica, de quinto a\u00f1o de escuela secundaria","volume":"103","author":"Valente","year":"2016","journal-title":"J. Argent. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103418","DOI":"10.1016\/j.bioorg.2019.103418","article-title":"Neurological and psychiatric management using COMT inhibitors: A review","volume":"94","author":"Akhtar","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s40263-021-00888-9","article-title":"COMT Inhibitors in the Management of Parkinson\u2019s Disease","volume":"36","author":"Fabbri","year":"2022","journal-title":"CNS Drugs"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nishikawa, N., Kwon, D.Y., Kogo, Y., Hatano, T., Cho, J.W., Kobayashi, C., Shiiba, H., Kim, J., Ishida, T., and Baik, J.S. (2025). Safinamide as an adjunct to levodopa monotherapy in Asian patients with Parkinson\u2019s disease experiencing early wearing-off: A pooled analysis of the J-SILVER and KEEP studies. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1591664"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s40263-015-0249-8","article-title":"Defining the role of the monoamine oxidase-B inhibitors for Parkinson\u2019s disease","volume":"29","author":"Robakis","year":"2015","journal-title":"CNS Drugs"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2047-9158-2-19","article-title":"Monoamine oxidase-B (MAO-B) inhibitors: Implications for disease-modification in Parkinson\u2019s disease","volume":"2","author":"Teo","year":"2013","journal-title":"Transl. Neurodegener."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1212\/WNL.67.7_suppl_2.S24","article-title":"Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition","volume":"67","author":"Stocchi","year":"2006","journal-title":"Neurology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"106088","DOI":"10.1016\/j.parkreldis.2024.106088","article-title":"Extended-release amantadine for OFF-related dystonia in Parkinson\u2019s disease","volume":"122","author":"Espay","year":"2024","journal-title":"Park. Relat. Disord."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1002\/mdc3.13347","article-title":"Antimuscarinic anticholinergic medications in Parkinson disease: To prescribe or deprescribe?","volume":"8","author":"Barrett","year":"2021","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1023\/B:JOBB.0000041771.66775.d5","article-title":"MPTP as a mitochondrial neurotoxic model of Parkinson\u2019s disease","volume":"36","author":"Przedborski","year":"2004","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s12974-018-1175-8","article-title":"Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson\u2019s disease","volume":"15","author":"Bao","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1517\/14728221003652489","article-title":"Targeting mitochondrial dysfunction in neurodegenerative disease: Part I","volume":"14","author":"Burchell","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1001\/jama.2021.10207","article-title":"Effect of urate-elevating inosine on early Parkinson disease progression: The SURE-PD3 randomized clinical trial","volume":"326","author":"Bluett","year":"2021","journal-title":"JAMA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.pharmthera.2005.02.002","article-title":"Therapeutic role of coenzyme Q10 in Parkinson\u2019s disease","volume":"107","author":"Shults","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"ref_57","first-page":"597","article-title":"Coenzyme Q10 effects in neurodegenerative disease","volume":"5","author":"Spindler","year":"2009","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.parkreldis.2015.05.022","article-title":"Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson\u2019s disease","volume":"21","author":"Yoritaka","year":"2015","journal-title":"Park. Relat. Disord."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1053\/meta.2002.31322","article-title":"Effect of inosine on the plasma concentration of uridine and purine bases","volume":"51","author":"Yamamoto","year":"2002","journal-title":"Metab.-Clin. Exp."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1177\/135245850100700507","article-title":"Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease","volume":"7","author":"Spitsin","year":"2001","journal-title":"Mult. Scler. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.2147\/TCRM.S139545","article-title":"Safinamide in the management of patients with Parkinson\u2019s disease not stabilized on levodopa: A review of the current clinical evidence","volume":"14","author":"Bette","year":"2018","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s40262-016-0449-5","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Safinamide","volume":"56","author":"Foley","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.parkreldis.2013.01.009","article-title":"Safinamide reduces dyskinesias and prolongs l-DOPA antiparkinsonian effect in parkinsonian monkeys","volume":"19","author":"Gregoire","year":"2013","journal-title":"Park. Relat. Disord."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.phrs.2003.12.004","article-title":"Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity","volume":"50","author":"Marzo","year":"2004","journal-title":"Pharmacol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/nan.12263","article-title":"Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson\u2019s disease","volume":"42","author":"Sadeghian","year":"2016","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1001\/archneur.59.10.1541","article-title":"Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline","volume":"59","author":"Shults","year":"2002","journal-title":"Arch. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Su\u00e1rez-Rivero, J.M., Pastor-Maldonado, C.J., Povea-Cabello, S., \u00c1lvarez-C\u00f3rdoba, M., Villal\u00f3n-Garc\u00eda, I., Munuera-Cabeza, M., Su\u00e1rez-Carrillo, A., Talaver\u00f3n-Rey, M., and S\u00e1nchez-Alc\u00e1zar, J.A. (2021). Coenzyme Q10 analogues: Benefits and challenges for therapeutics. Antioxidants, 10.","DOI":"10.3390\/antiox10020236"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Manzar, H., Abdulhussein, D., Yap, T.E., and Cordeiro, M.F. (2020). Cellular consequences of coenzyme Q10 deficiency in neurodegeneration of the retina and brain. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239299"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1146\/annurev-cellbio-101011-155750","article-title":"Functional diversity of laminins","volume":"28","author":"Domogatskaya","year":"2012","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1001\/jamaneurol.2014.131","article-title":"A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: No evidence of benefit","volume":"71","author":"Beal","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Zapata-Acevedo, J.F., Garc\u00eda-P\u00e9rez, V., Cabezas-P\u00e9rez, R., Losada-Barrag\u00e1n, M., Vargas-S\u00e1nchez, K., and Gonz\u00e1lez-Reyes, R.E. (2022). Laminin as a biomarker of blood\u2013brain barrier disruption under neuroinflammation: A systematic review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126788"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"eaal4165","DOI":"10.1126\/scisignal.aal4165","article-title":"Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP","volume":"10","author":"Zhang","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1212\/WNL.60.1.69","article-title":"Implanted intracerebroventricular glial cell line-derived neurotrophic factor: Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD","volume":"60","author":"Nutt","year":"2003","journal-title":"Neurology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/s41586-025-08700-0","article-title":"Phase I\/II trial of iPS-cell-derived dopaminergic cells for Parkinson\u2019s disease","volume":"641","author":"Sawamoto","year":"2025","journal-title":"Nature"},{"key":"ref_75","first-page":"875","article-title":"GDNF and Parkinson\u2019s disease: Where next? A summary from a recent workshop","volume":"10","author":"Barker","year":"2020","journal-title":"J. Park. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/S1474-4422(13)70025-5","article-title":"Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson\u2019s disease and motor fluctuations: A phase 3 randomised, double-blind trial","volume":"12","author":"Hauser","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nm850","article-title":"Direct brain infusion of glial cell line\u2013derived neurotrophic factor in Parkinson\u2019s disease","volume":"9","author":"Gill","year":"2003","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.parkreldis.2013.08.017","article-title":"Randomized trial of IPX066, carbidopa\/levodopa extended release, in early Parkinson\u2019s disease","volume":"20","author":"Pahwa","year":"2014","journal-title":"Park. Relat. Disord."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1756285617737728","DOI":"10.1177\/1756285617737728","article-title":"Extended-release oral capsule of carbidopa-levodopa in Parkinson\u2019s disease","volume":"11","author":"Margolesky","year":"2017","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S1474-4422(12)70049-2","article-title":"Treatment of motor and non-motor features of Parkinson\u2019s disease with deep brain stimulation","volume":"11","author":"Fasano","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s11065-022-09540-9","article-title":"Deep brain stimulation in Parkinson disease: A meta-analysis of the long-term neuropsychological outcomes","volume":"33","author":"Bucur","year":"2023","journal-title":"Neuropsychol. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Muthuraman, M., Koirala, N., Ciolac, D., Pintea, B., Glaser, M., Groppa, S., Tam\u00e1s, G., and Groppa, S. (2018). Deep brain stimulation and L-DOPA therapy: Concepts of action and clinical applications in Parkinson\u2019s disease. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00711"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.nec.2019.01.001","article-title":"Deep brain stimulation for Parkinson\u2019s disease","volume":"30","author":"Kogan","year":"2019","journal-title":"Neurosurg. Clin."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"968","DOI":"10.4103\/0028-3886.266268","article-title":"Deep brain stimulation in Parkinson\u2019s disease","volume":"67","author":"Malek","year":"2019","journal-title":"Neurol. India"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s12032-023-02293-2","article-title":"Pyroptosis in cancer treatment and prevention: The role of natural products and their bioactive compounds","volume":"41","author":"Wu","year":"2024","journal-title":"Med. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"109595","DOI":"10.1016\/j.biopha.2019.109595","article-title":"Pyroptosis: A new frontier in cancer","volume":"121","author":"Fang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.intimp.2018.12.019","article-title":"The mechanisms of NLRP3 inflammasome\/pyroptosis activation and their role in Parkinson\u2019s disease","volume":"67","author":"Wang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s11658-023-00516-y","article-title":"The pyroptosis mediated biomarker pattern: An emerging diagnostic approach for Parkinson\u2019s disease","volume":"29","author":"Liang","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Vizziello, M., Borellini, L., Franco, G., and Ardolino, G. (2021). Disruption of mitochondrial homeostasis: The role of PINK1 in Parkinson\u2019s disease. Cells, 10.","DOI":"10.3390\/cells10113022"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Chen, X., Wang, Q., Li, S., Li, X.J., and Yang, W. (2022). Mitochondrial-dependent and independent functions of PINK1. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.954536"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1093\/brain\/awaa246","article-title":"Mitochondrial damage-associated inflammation highlights biomarkers in PRKN\/PINK1 parkinsonism","volume":"143","author":"Borsche","year":"2020","journal-title":"Brain"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"118247","DOI":"10.1016\/j.lfs.2020.118247","article-title":"PINK1: The guard of mitochondria","volume":"259","author":"Wang","year":"2020","journal-title":"Life Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1021\/acsmedchemlett.3c00070","article-title":"Parkinson\u2019s disease: Are PINK1 activators inching closer to the clinic?","volume":"14","author":"Mehellou","year":"2023","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: Past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41392-023-01353-3","article-title":"Signaling pathways in Parkinson\u2019s disease: Molecular mechanisms and therapeutic interventions","volume":"8","author":"Yong","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"101890","DOI":"10.1016\/j.pneurobio.2020.101890","article-title":"Ferroptosis and its potential role in the physiopathology of Parkinson\u2019s Disease","volume":"196","author":"Bouchaoui","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.nbd.2016.05.011","article-title":"Ferroptosis, a newly characterized form of cell death in Parkinson\u2019s disease that is regulated by PKC","volume":"94","author":"Gouel","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00415-019-09486-8","article-title":"Zona incerta as a therapeutic target in Parkinson\u2019s disease","volume":"267","author":"Ossowska","year":"2020","journal-title":"J. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.tins.2019.11.007","article-title":"Zona incerta: An integrative node for global behavioral modulation","volume":"43","author":"Wang","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"108761","DOI":"10.1016\/j.isci.2023.108761","article-title":"Connecting the dots in the zona incerta: A study of neural assemblies and motifs of inter-area coordination in mice","volume":"27","author":"Londei","year":"2024","journal-title":"iScience"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"107149","DOI":"10.1016\/j.isci.2023.107149","article-title":"Chemogenetic and optogenetic stimulation of zona incerta GABAergic neurons ameliorates motor impairment in Parkinson\u2019s disease","volume":"26","author":"Chen","year":"2023","journal-title":"iScience"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/mds.27372","article-title":"International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson\u2019s disease","volume":"33","author":"Fox","year":"2018","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/mds.27602","article-title":"Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Medicine Committee. Update on treatments for nonmotor symptoms of Parkinson\u2019s disease-an evidence-based medicine review","volume":"34","author":"Seppi","year":"2019","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_104","unstructured":"Otsuka Pharmaceutical Co., Ltd. (2020). New Therapeutic Methods for the Treatment of Parkinson\u2019s Disease, JP6727259B2."},{"key":"ref_105","unstructured":"XenoPort Inc., and Arbor Pharmaceuticals LLC (2013). Pharmaceutical Compositions and Oral Dosage Forms of a Levodopa Prodrug and Methods of Use, US8435562B2."},{"key":"ref_106","unstructured":"AbbVie Inc (2024). Subcutaneously Administered Treatments for Advanced Parkinson\u2019s Disease, US20240100072A1."},{"key":"ref_107","unstructured":"Abtis Co., Ltd (2019). Coenzyme Q10 Solubilizing Composition and Method for Preparing the Same, US20190133969A1."},{"key":"ref_108","unstructured":"Lee, T.-Y. (2022). Pharmaceutical Compositions and Uses Thereof in Treating Parkinson\u2019s Disease, WO2022052016A1."},{"key":"ref_109","unstructured":"Portela, B., and Cia SA (2024). Treatment Regimens for Parkinson\u2019s Disease, WO2024039256A1."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/2\/226\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:13:49Z","timestamp":1772082829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/2\/226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,14]]},"references-count":109,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["brainsci16020226"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16020226","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,14]]}}}