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.

Nanotized Curcumin and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

“…1) was observed to be much smaller than that measured by DLS. This is because the TEM measures the absolute size of nanoparticles in a dry state, whereas DLS gives the hydrodynamic diameter, as reported earlier (37). Further, we examined the entrapment and loading efficiencies of curcumin in the polymeric formulation, which were found to be reasonably high owing to the hydrophobic nature of the drug.…”

“…A drop of the suspension was placed over a carbon-coated grid, negatively stained using uranyl acetate, and allowed to dry at room temperature. The grid was observed by using an transmission electron microscope (Tecnai G2 Spirit; FEI, Eindhoven, The Netherlands) at a working voltage of 80 kV using Gatan digital micrograph software (37).…”

Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson’s disease treatment

“…The difference in values between TEM and DLS measurements was ascribed to the state of NPs used for measurements. 23 The number of the introduced thiol groups was 1.44±0.02, which was within the optimal range of 1-2. Lf conjugation efficiency was 18.99%±2.32%.…”

“…23 In brief, 2 mL of NPs and Lf-NPs samples were encased in dialysis bags (molecular weight cutoff: 7 kDa), which were incubated in 30 mL phosphate buffer (pH 7.4) containing 0.5% (w/v) sodium dodecyl sulfate, with shaking in a water bath at 37°C. At prespecified time intervals, 1 mL of phosphate buffer was withdrawn from outside the dialysis bag, and an equivalent volume of release medium was supplemented.…”

Neuroprotective Investigation of Chitosan Nanoparticles for Dopamine Delivery

“…However, this leads to several undesired side-effects. Thus, to reduce the occurrence of side-effects, the delivery of DA has been attempted in various ways through nanotechnological approaches [5,15,17,20,21].…”