Parkinson's disease is a progressive neurodegenerative disease affecting more than 10 million patients worldwide. The leading cause of this pathological condition is an imbalance between dopaminergic and cholinergic systems due to dopaminergic neurons' degeneration in the nigrostriatal pathways. The primary goal of Parkinson's therapy is to correct the levels of the mentioned neurotransmitters, and the administration of Levodopa has been accepted as a "gold standard" treatment. The amino acid precursor can successfully control the symptoms by compensating for the reduced concentration of endogenous dopamine and activating postsynaptic D-receptors in the striatum.
The intensive enzymatic degradation of levodopa in the gastrointestinal tract is the main reason for its low concentration in the midbrain (~1%) and the increased frequency of adverse drug reactions. Despite numerous attempts to improve clinical efficacy, increasing bioavailability and reducing side effects remain difficult. This makes it necessary to use innovative drug delivery systems capable of overcoming the problems mentioned above.
This literature review presents new technological approaches for improved delivery of levodopa to the central nervous system. Nanoparticles, liposomes, cyclodextrin complexes, carbon nanotubes, and others represent promising platforms for the delivery and controlled release of the dopamine precursor. With the ability to ensure optimal bioavailability, constant plasma concentration, minimal peripheral degradation, and reduced adverse drug reactions, they successfully overcome the shortcomings of conventional levodopa-containing dosage forms.
Abbott RD, Ross GW, White LR, Nelson JS, Masaki KH, Tanner CM, et al. Midlife adiposity and the future risk of Parkinson’s disease. Neurology. 2002;59(7):1051-57.
Abbott A. Levodopa: the story so far. Nature. 2010;446(7310):S6-7.
Abbott RD, Ross GW, Petrovitch H, Masaki KH, Launer LJ, Nelson JS, et al. Midlife milk consumption and substantia nigra neuron density at death. Neurology. 2016;86(6):512-19.
Ahmad MZ, Sabri AHB, Anjani QK, Domínguez-Robles J, Abdul Latip N, Hamid KA. Design and Development of Levodopa Loaded Polymeric Nanoparticles for Intranasal Delivery. Pharmaceuticals (Basel). 2022;15(3):370.
Anouti A, Koller WC. Tremor disorders. Diagnosis and management. West J Med 1995;162(6):510-3.
Ansari AQ, Ansari SJ, Khan MQ, Khan MF, Qureshi UA, Khatri Z, et al. Electrospun Zein nanofibers as drug carriers for controlled delivery of Levodopa in Parkinson syndrome. Mater Res. 2019;6:075405.
Archibald NK, Clarke MP, Mosimann UP, Burn DJ. Visual symptoms in Parkinson’s disease and Parkinson’s disease dementia. Mov Disord. 2011;26(13):2387-95.
Arisoy S, Sayiner O, Comoglu T, Onal D, Atalay O, Pehlivanoglu B. 2020. In vitro and in vivo evaluation of levodopa-loaded nanoparticles for nose to brain delivery. Pharm Dev Technol. 2020;25(6):735-47.
Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 2016;15(12):1257-72.
Bertoldi M. Mammalian Dopa decarboxylase: structure, catalytic activity and inhibition. Arch Biochem Biophys. 2014;546:1-7.
Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B. Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to bedside gap. Lancet Neurol. 2010;9(11):1106-17.
Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8(5):464-74.
Chen H, Zhang SM, Schwarzschild MA, Hernán MA, Willett WC, Ascherio A. Obesity and the risk of Parkinson’s disease. Am J Epidemiol. 2004;159(6):547-55.
Chen H, O’Reilly E, McCullough ML, Rodriguez C, Schwarzschild MA, Calle EE, et al. Consumption of dairy products and risk of Parkinson’s disease. Am J Epidemiol 2007;165(9):998-1006.
Connolly B, Lang AE. Pharmacological treatment of Parkinson’s disease: a review. JAMA. 2014;311(16):1670-83.
Cosgrove J, Alty JE, Jamieson S. Cognitive impairment in Parkinson’s disease. Postgrad Med J. 2015;91(1074):212-20.
De Castro KC, Costa JM, Campos MGN. Drug-loaded polymeric nanoparticles: a review. Int J Polym Mater. 2020;71(1):1-13.
De Virgilio A, Greco A, Fabbrini G, Inghilleri M, Rizzo MI, Gallo A, et al. Parkinson’s disease: autoimmunity and neuroinflammation. Autoimmun Rev. 2016;15(10):1005-11.
DeMaagd G, Philip A. Parkinson’s disease and its management: Part 1: Disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. Pharm Ther. 2015;40(8):504-10,532.
Draoui A, El Hiba O, Abdelaati EK, Abbaoui A, El Fari R, Aitihya M, et al. Differential impairment of short working and spatial memories in a rat model of progressive Parkinson’s disease onset: a focus on the prodromal stage. Brain Res Bull. 2019;150:307-16.
Draoui A, El Hiba O, Aimrane A, El Khiat A, Gamrani H. Parkinson’s disease: from bench to bedside. Rev Neurol (Paris). 2020;176(7-8):543-55.
Driver JA, Smith A, Buring JE, Gaziano JM, Kurth T, Logroscino G. Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care. 2008;31(10):2003-5.
Espay AJ, Morgante F, Merola A, Fasano A, Marsili L, Fox SH, et al. Levodopa-Induced Dyskinesia in Parkinson Disease: Current and Evolving Concepts. Ann Neurol. 2018;84(6):797-811.
Fox SH, Katzenschlager R, Lim S-Y, Ravina B, Seppi K, Coelho M et al. The Movement Disorder Society evidence-based medicine review update: treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2011;26:S2-41.
Garbayoa E, Ansorena E, Blanco-Prieto M.J. Drug development in Parkinson’s disease: From emerging molecules to innovative drug delivery systems. Maturitas. 2013;76(3):272-78.
Gurturka Z, Tezcanera A, Dalgicb AD, Korkmazd S, Keskin D. Maltodextrin modified liposome for drug delivery through blood brain barrier. MedChemComm. 2017;8(6):1337-45.
Henderson EJ, Lord SR, Close JCT, Lawrence AD, Whone A, Ben-Shlomo Y. The ReSPonD trial – rivastigmine to stabilise gait in Parkinson’s disease a phase II, randomised, double blind, placebo controlled trial to evaluate the effect of rivastigmine on gait in patients with Parkinson’s disease who have fallen. BMC Neurol. 2013;13(1):188.
Hu G, Jousilahti P, Nissinen A, Antikainen R, Kivipelto M, Tuomilehto J. Body mass index and the risk of Parkinson disease. Neurology. 2006;67(11):1955-9.
Jost WH. Nonmotor symptoms in Parkinson’s disease. Nervenarzt. 2017;88(8):874-87.
Kalia LV, Lang A.E. Parkinson’s disease, Lancet. 2015;386(9996):896-912.
Kulisevsky J. Role of dopamine in learning and memory implications for the treatment of cognitive dysfunction in patients with Parkinson’s disease. Drugs Aging. 2000;16(5):365-79.
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979-80.
Li SD, Huang L. Stealth nanoparticles: high density but sheddable PEG is a key for tumor targeting. J Control Release. 2010;145(3):178-81.
Marras C, Hincapié CA, Kristman VL, Cancelliere C, Soklaridis S, Li A, et al. Systematic review of the risk of Parkinson’s disease after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95:S238-44.
Mishra A, Goel RK. Chronic 5-HT3 receptor antagonism ameliorates seizures and associated memory deficit in pentylenetetrazole-kindled mice. Neuroscience. 2016;339:319-28.
Mishra A, Goel RK. Modulatory Effect of Serotonergic System in Pentylenetetrazole-Induced Seizures and Associated Memory Deficit: Role of 5- HT1A and 5-HT2A/2C. J Epilepsy Res. 2019;9(2):119-25.
Mogharbel BF, Cardoso MA, Irioda AC, Stricker PEF, Slompo RC, Appel JM, et al. Biodegradable Nanoparticles Loaded with Levodopa and Curcumin for Treatment of Parkinson’s Disease. Molecules. 2022;27(9):2811.
More JC, Nistico R, Dolman NP, Clarke VR, Alt AJ, Ogden AM, Buelens FP. Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist. Neuropharmacology. 2004;47(1):46-64.
Ovallath, S, Sulthana, B. Levodopa: History and Therapeutic Applications. Ann Indian Acad Neurol. 2017;20(3):185-9.
Pandey S, Srivanitchapoom P. Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management. Ann Indian Acad Neurol. 2017;20(3):190-8.
Paul A, Yadav KS. Parkinson's disease: Current drug therapy and unraveling the prospects of nanoparticles. J Drug Del Sci Technol. 2020;58:101790.
Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant off spring of patients with type 2 diabetes. N Engl J Med. 2004;350(7):664-71.
Pfeiffer RF. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2016;22:S119-22.
Plaza-Oliver M, Santander-Ortega MJ, Lozano MV. Current approaches in lipid-based nanocarriers for oral drug delivery. Drug Deliv Transl Res. 2021;11(2):471-97.
Ribovski L, Hamelmann NM, Paulusse JMJ. Polymeric Nanoparticles Properties and Brain Delivery. Pharmaceutics. 2021;13(12):2045.
Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, Bezard E, et al. Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol. 2009;8(12):1128-39.
Sakakibara R, Tateno F, Kishi M, Tsuyuzaki Y, Uchiyama T, Yamamoto T. Pathophysiology of bladder dysfunction in Parkinson’s disease. Neurobiol Dis. 2012;46(3):565-71.
Samir A, Elgamal BM, Gabr H, Sabaawy HE. Nanotechnology applications in hematological malignancies (Review). Oncol Rep. 2015;34(3):1097-105.
Schapira AHV, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov. 2006;5(10):845-54.
Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017;18(7):435-50.
Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B. Diabetes and the risk of developing Parkinson’s disease in Denmark. Diabetes Care. 2011;34(5):1102-8.
Sharma S, Lohan S, Murthy RSR. Formulation and characterization of intranasal mucoadhesive nanoparticulates and thermo-reversible gel of levodopa for brain delivery. Drug Dev Ind Pharm. 2014;40(7):869-78.
Simon KC, Chen H, Schwarzschild M, Ascherio A. Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease. Neurology. 2007; 69(17):1688-95.
Singh S. Nanomedicine–Nanoscale Drugs and Delivery Systems. J Nanosci Nanotechnol. 2010;10(12):7906-18.
Smith Y, Wichmann T, Factor SA, DeLong MR. Parkinson’s disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharmacology. 2012;37(1):213-46.
Sofian ZМ, Shafee SS, Abdullah JM, Osman H, Razak SA. Evaluation of the Cytotoxicity of Levodopa and its Complex with Hydroxypropyl-ß-Cyclodextrin (HP-ß-CD) to an Astrocyte Cell Line. Malays J Med Sci. 2014;21(Spec Issue):6-11.
Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson's Disease: Current Status and Future Developments. Curr Neuropharmacol. 2018;16(8):1239-52.
Tan JM, Saifullah B, Kura AY, Fakurazi S, Hussein MZ. Incorporation of Levodopa into Biopolymer Coatings Based on Carboxylated Carbon Nanotubes for pH-Dependent Sustained Release Drug Delivery. Nanomaterials. 2018;8(6):389.
Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect. 2011;119(6):866-72.
Tibar H, El Bayad K, Bouhouche A, Haddou EHA Ben, Benomar A, Yahyaoui M, et al. Non-motor symptoms of Parkinson’s Disease and their impact on quality of life in a cohort of Moroccan patients. Front Neurol. 2018;9:170.
Tiwari SB, Amiji MM. A review of nanocarrier-based CNS delivery systems. Curr Drug Deliv. 2006;3(2):219-32.
Uwishema O, Onyeaka H, Badri R, Yücel AN, Korkusuz AK, Ajagbe AO, et al. The understanding of Parkinson’s disease through genetics and new therapies. Brain Behav. 2022;12(5):e2577.
Vega-Vásquez P, Mosier NS, Irudayaraj J. Nanoscale Drug Delivery Systems: From Medicine to Agriculture. Front Bioeng Biotechnol. 2020;8:79.
Wills AM, Rousha L, Pe´rez A, Ren X, Boyd J. Predictors of weight loss in early treated Parkinson’s disease from the NET-PD LS-1 cohort. J Neurol. 2017;264(8):1746-53.
Xiang Y, Wu Q, Liang L, Wang X, Wang J, Zhang X, et al. Chlorotoxin-modified stealth liposomes encapsulating levodopa for the targeting delivery against Parkinson's disease in the MPTP-induced mice model. J Drug Target. 2012;20(1):67-75.
Yang W, Hamilton JL, Kopil C, et al. Current and projected future economic burden of Parkinson's disease in the U.S. NPJ Parkinsons Dis. 2020;6:15.
Yang X, Zheng R, Cai Y, Liao M, Yuan W, Liu Z. Controlled-release levodopa methyl ester/benserazide-loaded nanoparticles ameliorate levodopa-induced dyskinesia in rats. Int J Nanomedicine. 2012;7:2077-86.
Zhang X, Song D, Gu L, Ren Y, Verkhratsky A, Peng L. Decrease of gene expression of astrocytic 5-HT2B receptors parallels development of depressive phenotype in a mouse model of Parkinson’s disease. Front Cell Neurosci. 2015;9:388.
