Trans-Blood Brain Barrier Delivery of Dopamine-Loaded Nanoparticles Reverses Functional Deficits in Parkinsonian Rats

• Published in: ACS nano Vol. 9; no. 5; pp. 4850 - 4871
• Main Authors: Pahuja, Richa, Seth, Kavita, Shukla, Anshi, Shukla, Rajendra Kumar, Bhatnagar, Priyanka, Chauhan, Lalit Kumar Singh, Saxena, Prem Narain, Arun, Jharna, Chaudhari, Bhushan Pradosh, Patel, Devendra Kumar, Singh, Sheelendra Pratap, Shukla, Rakesh, Khanna, Vinay Kumar, Kumar, Pradeep, Chaturvedi, Rajnish Kumar, Gupta, Kailash Chand
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.05.2015
• Subjects: Animals; Blood-Brain Barrier - metabolism; Cell Line, Tumor; Dopamine - adverse effects; Dopamine - chemistry; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Drug Carriers - adverse effects; Drug Carriers - chemistry; Drug Carriers - metabolism; Drug Liberation; Humans; Lactic Acid - chemistry; Nanoparticles - chemistry; Neostriatum - drug effects; Neostriatum - metabolism; Oxidation-Reduction; Oxidopamine - chemistry; Oxidopamine - pharmacology; Oxidopamine - therapeutic use; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Polyglycolic Acid - chemistry; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Wistar; Receptors, Dopamine - metabolism; Safety; Up-Regulation - drug effects; nanoparticles; dopamine; Parkinson’s disease; tyrosine hydroxylase
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/nn506408v

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.