Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self-regenerative capacity. Curcumin, a neuroprotective agent, has poor brain bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin, and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/β-catenin pathway, involved in regulation of neurogenesis. These nanoparticles caused enhanced nuclear translocation of β-catenin, decreased GSK-3β levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA-mediated genetic inhibition of the Wnt pathway blocked neurogenesis-stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD-like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk, and GSK-3β. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self-repair mechanism.

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.

Oxidative stress is reported as one of the most widely accepted mechanisms of maneb (MB)- and paraquat (PQ)-induced nigrostriatal dopaminergic neurodegeneration leading to the Parkinson's disease (PD) phenotype. The study investigated the effects of silymarin, an antioxidant of plant origin, and melatonin, an indoleamine produced in all species, in MB- and PQ-induced mouse model of PD. The mice were treated intraperitoneally daily with silymarin (40mg/kg) or melatonin (30mg/kg) along with respective controls for 9wk. Subsets of these animals were also treated with MB (30mg/kg) and PQ (10mg/kg), twice a week, for 9wk, 2hr after silymarin/melatonin treatment. Locomotor activities along with striatal dopamine content, tyrosine hydroxylase (TH) immunoreactivity, number of degenerating neurons, lipid peroxidation and nitrite content were estimated. Additionally, mRNA expression of vesicular monoamine transporter, cytochrome P-450 2E1 (CYP2E1), and glutathione-S-transferase A4-4 (GSTA4-4), catalytic activities of CYP2E1 and GSTA4-4 and protein expressions of unphosphorylated and phosphorylated p53 (p53 and P-p53), Bax and caspase 9 were measured in control and MB- and PQ-treated mice with either silymarin or melatonin treatments. Silymarin/melatonin significantly offset MB- and PQ-mediated reductions in locomotor activities, dopamine content, TH immunoreactivity, VMAT 2 mRNA expression and the expression of p53 protein. Silymarin/melatonin attenuated the increases in lipid peroxidation, number of degenerating neurons, nitrite content, mRNA expressions of cytochrome P-450 2E1 (CYP2E1) and GSTA4-4, catalytic activities of CYP2E1 and GST and P-p53, Bax and caspase 9 protein expressions. The results demonstrate that silymarin and melatonin offer nigrostriatal dopaminergic neuroprotection against MB- and PQ-induced PD by the modulation of oxidative stress and apoptotic machinery.

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Parkinson's disease (PD) is one of the most common neurodegenerative disorders with limited clinical interventions. A number of epidemiological as well as case-control studies have revealed an association between pesticide exposure, especially of paraquat (PQ) and occurrence of PD. Hsp70, a molecular chaperone by function, has been shown as one of the modulators of neurological disorders. However, paucity of information regarding the protective role of Hsp70 on PQ-induced PD like symptoms led us to hypothesize that modulation of hsp70 expression in the dopaminergic neurons would improve the health of these cells. We took advantage of Drosophila, which is a well-established model for neurological research and also possesses genetic tools for easy manipulation of gene expression with limited ethical concern. Over-expression of hsp70 was found to reduce PQ-induced oxidative stress along with JNK and caspase-3 mediated dopaminergic neuronal cell death in exposed organism. Further, anti-apoptotic effect of hsp70 was shown to confer better homeostasis in the dopaminergic neurons of PQ-exposed organism as evidenced by their improved locomotor performance and survival. The study has merit in the context of human concern since we observed protection of dopaminergic neurons in PQ-exposed organism by over-expressing a human homologue of hsp70, HSPA1L, in these cells. The effect was parallel to that observed with Drosophila hsp70. These findings reflect the potential therapeutic applicability of hsp70 against PQ-induced PD like symptoms in an organism.

Environmental toxicants viz lead or cadmium and phthalate esters (di(2-ethylhexyl) phthalate [DEHP], dibutyl phthalate [DBP], and diethyl phthalate [DEP]) widely found in different environmental strata are linked to deteriorating male reproductive health. The objective was to assess the relationships between the seminal lead, cadmium, and phthalate (DEHP, DBP, DEP) concentrations at environmental level and serum hormone levels and semen quality in non-occupationally exposed men and specify the effect of individual and combined exposure of toxicants on semen quality. A study of 60 male partners of couples attending the Andrology Laboratory of the Reproductive Biology Department, All India Institute of Medical Sciences (AIIMS), New Delhi, India for semen analysis to assess their inability to achieve a pregnancy was selected for the study. The results of univariate and stepwise multiple regression analysis in the unadjusted model showed a significant correlation between lead or cadmium and phthalates DEHP/DBP/DEP and sperm motility, sperm concentration, and DNA damage. After adjusting for potential confounders, an association with lead or DEHP was only observed. The present data shows that lead (Pb) or cadmium (Cd) or phthalates might independently contribute to decline in semen quality and induce DNA damage. Phthalates might influence reproductive hormone testosterone. These findings are significant in light of the fact that men are exposed to a volley of chemicals; however, due to the small sample size, our finding needs to be confirmed in a larger population.

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