Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra, and oxidative stress is thought to contribute to this pathogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway, which induces the production of antioxidant enzymes, is thereby a potential target for therapeutics to reduce neurodegeneration in PD. Previously, we identified TPNA10168 from a chemical library as an activator of the Nrf2–ARE pathway, and the present study examined the effects of TPNA10168 on an in vivo PD model. Subcutaneous administration of TPNA10168 was associated with inhibited dopaminergic neuronal loss and behavioral impairment in 6-hydroxydopamine–induced PD model mice. Heme oxygenase-1 (HO-1) is an antioxidant enzyme expressed downstream of the Nrf2–ARE signaling pathway, and we observed that HO-1 protein levels were upregulated by TPNA10168 in the mouse brain. These results suggest that TPNA10168 inhibits dopaminergic neuronal death in PD model mice, and that upregulation of HO-1 might participate in this effect.

帕金森氏病（PD）是一种神经退行性疾病，其特征是黑质中多巴胺能神经元的选择性丢失，氧化应激被认为是导致这种发病机理的原因。核因子类胡萝卜素2相关因子2（Nrf2）-抗氧化反应元件（ARE）途径可诱导抗氧化酶的产生，因此是减少PD中神经变性的治疗方法的潜在靶标。以前，我们从化学文库中鉴定出TPNA10168是Nrf2-ARE途径的激活剂，并且本研究研究了TPNA10168对体内PD模型的影响。皮下注射TPNA10168与6-羟基多巴胺诱导的PD模型小鼠的多巴胺能神经元丢失和行为受损有关。血红素加氧酶-1（HO-1）是在Nrf2-ARE信号通路下游表达的一种抗氧化酶，我们观察到TPNA10168在小鼠脑中上调了HO-1蛋白的水平。这些结果表明，TPNA10168抑制了PD模型小鼠的多巴胺能神经元死亡，而HO-1的上调可能参与了这一作用。