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.

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Pyrethroid-based mosquito repellents (MR) are commonly used to protect humans against mosquito vector. New born babies and children are often exposed to pyrethroids for long periods by the use of liquid vaporizers. Occupational and experimental studies indicate that pyrethroids can cause clinical, biochemical and neurological changes, and that exposure to pyrethroids during organogenesis and early developmental period is especially harmful. The neurotoxicity caused by MR has aroused concern among public regarding their use. In the present study, the effect of exposure of rat pups during early developmental stages to a pyrethroid-based MR (allethrin, 3.6% w/v, 8h per day through inhalation) on blood-brain barrier (BBB) permeability was investigated. Sodium fluororescein (SF) and Evan's blue (EB) were used as micromolecular and macromolecular tracers, respectively. Exposure during prenatal (gestation days 1-20), postnatal (PND1-30) and perinatal (gestation days 1-20 + PND1-30) periods showed significant increase in the brain uptake index (BUI) of SF by 54% (P < 0.01), 70% (P < 0.01), 79% (P < 0.01), respectively. This increase persisted (68%, P < 0.01) even 1 week after withdrawal of exposure (as assessed on PND37). EB did not exhibit significant change in BBB permeability in any of the group. The results suggest that MR inhalation during early prenatal/postnatal/perinatal life may have adverse effects on infants leading to central nervous system (CNS) abnormalities, if a mechanism operates in humans similar to that in rat pups.

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Among trophic factors already known, glial cell line-derived neurotrophic factor (GDNF) and other members of its family have potent and specific action on dopaminergic neurons. In the present investigation an attempt has been made to validate the role of GDNF co-transplantation with fetal ventral mesencephalic cells (VMC) on functional viability and restoration using neurobehavioral, neurochemical and immunohistochemical parameters at 6 weeks post-transplantation in 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). A significant restoration (P<0.01) in D-amphetamine induced rotations, spontaneous and apomorphine induced locomotor activity in rats co-transplanted with VMC and GDNF was observed as compared to VMC alone transplanted rats. Level of dopamine (DA), 3,4-dihydroxy-phenyl acetic acid (DOPAC) and dopamine D2 (DA-D2) receptors in the caudate putamen (CPu) were significantly (P<0.001) restored in co-transplanted group as compared to VMC transplanted or GDNF administered animals. The functional viability of transplanted VMC was confirmed by tyrosine hydroxylase (TH) expression and quantification of TH-positive cells by image analysis revealed a significant restoration in TH-IR fibers density as well as TH-IR neurons counts in co-transplanted animals over VMC transplanted animals. Results suggest that co-transplantation of VMC and GDNF may be a better approach towards functional restoration in 6-OHDA lesioned rat model of Parkinson's disease.