Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3b) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3b activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3b phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6-OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3b signaling.

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Parkinson’s disease (PD) is a common neurodegenerative disease characterized the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Brain endogenous morphine biosynthesis was reported to be impaired in PD patients and exogenous morphine attenuated 6-hydroxydopamine (6-OHDA)-induced cell death in vitro. However, the mechanisms underlying neuroprotection of morphine in PD are still unclear. In the present study, we investigated the neuroprotective effects of low-dose morphine in cellular and animal models of PD and the possible underlying mechanisms. Herein, we found 6-OHDA and rotenone decreased the mRNA expression of key enzymes involved in endogenous morphine biosynthesis in SH-SY5Y cells. Incubation of morphine prevented 6-OHDA-induced apoptosis, restored mitochondrial membrane potential, and inhibited the accumulation of intracellular reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, morphine attenuated the 6-OHDA-induced endoplasmic reticulum (ER) stress possible by activating autophagy in SH-SY5Y cells. Finally, oral application of low-dose morphine significantly improved midbrain tyrosine hydroxylase (TH) expression, decreased apomorphine-evoked rotation and attenuated pain hypersensitivity in a 6-OHDA-induced PD rat model, without the risks associated with morphine addiction. Feeding of low-dose morphine prolonged the lifespan and improved the motor function in several transgenic Drosophila PD models in gender, genotype, and dose-dependent manners. Overall, our results suggest that neuroprotection of low-dose morphine may be mediated by attenuating ER stress and oxidative stress, activating autophagy, and ameliorating mitochondrial function.

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