title: Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats.
abstract: Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats.
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.|§Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Pahuja
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
authors.forename: Kavita
authors.initials: K
authors.lastname: Seth
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
authors.forename: Anshi
authors.initials: A
authors.lastname: Shukla
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
authors.forename: Rajendra Kumar
authors.initials: RK
authors.lastname: Shukla
authors.forename: Priyanka
authors.initials: P
authors.lastname: Bhatnagar
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
authors.forename: Lalit Kumar Singh
authors.initials: LK
authors.lastname: Chauhan
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
authors.forename: Prem Narain
authors.initials: PN
authors.lastname: Saxena
authors.affiliation: ∥CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226001, India.
authors.forename: Jharna
authors.initials: J
authors.lastname: Arun
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.|§Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Bhushan Pradosh
authors.initials: BP
authors.lastname: Chaudhari
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.|§Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Patel
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.
authors.forename: Sheelendra Pratap
authors.initials: SP
authors.lastname: Singh
authors.affiliation: §Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.|∥CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226001, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.|§Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Khanna
authors.affiliation: §Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.|§Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
authors.affiliation: †CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80 MG Marg, Lucknow 226001, India.|§Academy of Scientific and Innovative Research (AcSIR), Delhi 110001, India.
authors.forename: Kailash Chand
authors.initials: KC
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D045744:Cell Line, Tumor; D004298:Dopamine / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism; D004337:Drug Carriers / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D065546:Drug Liberation; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism; D012449:Safety; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004337:Drug Carriers; D011954:Receptors, Dopamine; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016627:Oxidopamine; D004298:Dopamine
keywords: Parkinson’s disease; dopamine; nanoparticles; tyrosine hydroxylase