Yue Peijian, Gao Lin, Wang Xuejing, Ding Xuebing, Teng Junfang
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, China.
Department of Neurological Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Neurochem Res. 2017 May;42(5):1366-1374. doi: 10.1007/s11064-017-2184-1. Epub 2017 Feb 28.
Glial cell line-derived neurotrophic factor (GDNF) plays important roles in protecting the damaged or dying dopamine neurons in the animal models of Parkinson's disease (PD). This study was to determine the effect and mechanisms of GDNF on the apoptosis of neurons in 6-hydroxydopamine (6-OHDA) induced Parkinson's disease model of rats. Healthy male Sprague-Dawley rats (220-240 g) were randomly divided into six groups (n = 10). 6-OHDA was used to establish the PD rat model. Tyrosine hydroxylase (TH) immunohistochemistry was used to assess the neuron loss in 6-OHDA-lesioned rats. TUNEL and western blot were used to identify the effects and mechanisms of GDNF in the rat model of PD. The numbers of TH-positive neurons in the 6-OHDA-injected lesioned substantia nigra (SN) decreased significantly compared with the Sham group. GDNF treatment effectively ameliorated the apoptosis of neuronal cells in SN induced by 6-OHDA. In addition, GDNF significantly increased serine protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) phosphorylation induced by 6-OHDA. In contrast, application of LY294002 or triciribine reversed the roles of GDNF in PD models. The results implicated that the anti-apoptosis effects of GDNF in neurons might be mediated through PI3K/Akt/GSK3β pathway. Therefore, GDNF may be a promising agent for PD treatment.
胶质细胞源性神经营养因子（GDNF）在帕金森病（PD）动物模型中对受损或濒死的多巴胺能神经元具有重要的保护作用。本研究旨在确定GDNF对6-羟基多巴胺（6-OHDA）诱导的大鼠帕金森病模型中神经元凋亡的影响及其机制。将健康雄性Sprague-Dawley大鼠（220-240 g）随机分为六组（n = 10）。采用6-OHDA建立PD大鼠模型。酪氨酸羟化酶（TH）免疫组织化学法评估6-OHDA损伤大鼠的神经元损失。TUNEL法和蛋白质免疫印迹法用于确定GDNF在PD大鼠模型中的作用及机制。与假手术组相比，6-OHDA注射损伤侧黑质（SN）中TH阳性神经元数量显著减少。GDNF治疗有效改善了6-OHDA诱导的SN区神经细胞凋亡。此外，GDNF显著增加了6-OHDA诱导的丝氨酸蛋白激酶B（Akt）和糖原合酶激酶3β（GSK3β）的磷酸化。相反，应用LY294002或曲古抑菌素A可逆转GDNF在PD模型中的作用。结果表明，GDNF对神经元的抗凋亡作用可能是通过PI3K/Akt/GSK3β信号通路介导的。因此，GDNF可能是一种有前景的PD治疗药物。
