Li Xiao-Huan, Dai Chun-Fang, Chen Long, Zhou Wei-Tao, Han Hui-Li, Dong Zhi-Fang
Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
CNS Neurosci Ther. 2016 Jul;22(7):617-24. doi: 10.1111/cns.12555. Epub 2016 Apr 15.
Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and diminished dopamine content in the striatum, which is at least partly associated with α-synuclein protein overexpression in these neurons. Recent reports show that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects in animal model of PD. However, it is unclear whether the therapeutic effects of DHF are associated with the expression of α-synuclein.
In this study, we investigated the protective effects of DHF on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced deficit of motor functions, the loss of dopaminergic neurons and the expression of α-synuclein as well as antioxidative activity in the C57BL/6 mice.
Mice were treated with MPTP (30 mg/kg, i.p.) once a day for 5 days to induce dopaminergic neuron death in the SN. DHF (5 mg/kg, i.p.) was administrated once a day from the first day of MPTP injection until 9 days after the last injection of MPTP. Behavioral tests showed that DHF succeeded in ameliorating the impaired motor functions in the MPTP-treated mice. The immunohistochemical assay showed that the amelioration of motor function was accompanied by a reduction in the loss of dopaminergic neurons in the SN and striatum. Western blot analyses showed that DHF prevented the inactivation of TrkB and suppressed α-synuclein overexpression in the SN and striatum following MPTP treatment. Antioxidative activity detection revealed that DHF prevented MPTP-induced reduction in glutathione and total superoxide dismutase activity in the SN and striatum.
Taken together, these results indicate that DHF treatment may suppress the accumulation of α-synuclein and oxidative stress via activating TrkB and subsequently block the loss of dopaminergic neurons in the SN and striatum, thereby ameliorating MPTP-induced motor deficits in the C57BL/6 mice.
帕金森病（PD）是一种神经退行性疾病，其特征是黑质（SN）中多巴胺能神经元丧失以及纹状体中多巴胺含量减少，这至少部分与这些神经元中α-突触核蛋白的过表达有关。最近的报告显示，TrkB激动剂7,8-二羟基黄酮（DHF）在PD动物模型中具有有益作用。然而，尚不清楚DHF的治疗效果是否与α-突触核蛋白的表达有关。
在本研究中，我们研究了DHF对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的C57BL/6小鼠运动功能缺陷、多巴胺能神经元丧失、α-突触核蛋白表达以及抗氧化活性的保护作用。
小鼠每天腹腔注射一次MPTP（30 mg/kg），持续5天，以诱导SN中多巴胺能神经元死亡。从MPTP注射的第一天开始，每天腹腔注射一次DHF（5 mg/kg），直到最后一次注射MPTP后9天。行为测试表明，DHF成功改善了MPTP处理小鼠的运动功能受损。免疫组织化学分析表明，运动功能的改善伴随着SN和纹状体中多巴胺能神经元丧失的减少。蛋白质免疫印迹分析表明，DHF可防止MPTP处理后TrkB的失活，并抑制SN和纹状体中α-突触核蛋白的过表达。抗氧化活性检测显示，DHF可防止MPTP诱导的SN和纹状体中谷胱甘肽和总超氧化物歧化酶活性的降低。
综上所述，这些结果表明，DHF治疗可能通过激活TrkB来抑制α-突触核蛋白的积累和氧化应激，随后阻止SN和纹状体中多巴胺能神经元的丧失，从而改善MPTP诱导的C57BL/6小鼠的运动缺陷。
