Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/GSK3β signaling pathway
Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/GSK3β signaling pathway
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DOI：
10.1111/jnc.12038
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发表时间：
2012-12-01
影响因子：
4.7
通讯作者：
Luo, Wei-Feng
中科院分区：
文献类型：
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作者：
Gong, Li;Zhang, Qi-Lin;Luo, Wei-Feng
据报道，较高的血浆尿酸盐水平与帕金森病（PD）的风险降低和进展缓慢有关。本研究探讨了尿酸盐对6-羟基多巴胺（6-OHDA）单侧损毁大鼠黑质纹状体通路多巴胺能神经元的影响。尿酸（UA）以200 mg/kg每日两次连续10天腹腔注射，使血浆和纹状体中尿酸盐（UA的阴离子形式）分别比溶剂组升高55%和36.8%。发现UA的该方案改善黑质纹状体系统中的行为缺陷、多巴胺能神经元损失以及多巴胺耗竭。此外，尿酸管理能够提高谷胱甘肽水平和超氧化物歧化酶活性，而减少丙二醛积累的纹状体。此外，与假手术大鼠相比，6-OHDA损伤大鼠的损伤纹状体中蛋白激酶B（Akt）和糖原合成酶激酶3 β（GSK 3 β）的磷酸化显著降低。在接受UA治疗的帕金森病大鼠中，这种减少有所减弱。同样，体外研究结果表明，UA缓解了6-OHDA引起的Akt活化的降低和GSK 3 β活性的增加。此外，发现在PI 3 K抑制剂存在下，尿酸盐的神经保护作用及其对GSK 3 β Ser 9磷酸化的调节被消除。因此，我们的研究结果表明，尿酸盐能够保护大鼠黑质纹状体通路中的多巴胺能神经元免受6-OHDA的神经毒性，并表明其有益作用可能与其调节Akt/GSK 3 β信号有关。
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 200mg/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 (GSK3 beta) 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 GSK3 beta activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3 beta 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/GSK3 beta signaling.