Tai Wenjiao, Ye Xuan, Bao Xiuqi, Zhao Baozhong, Wang Xiaoliang, Zhang Dan
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Neuropharmacology. 2013 Dec;75:201-12. doi: 10.1016/j.neuropharm.2013.07.020. Epub 2013 Aug 2.
The participation of neuroinflammation in the pathogenesis of Parkinson's disease (PD) has long been validated. Excessive activated microglia release a large number of pro-inflammatory factors, damage surrounding neurons and eventually induce neurodegeneration. Inhibition of microglial over-activation might be a promising strategy for PD treatment. FLZ (formulated as: N-(2-(4-hydroxy-phenyl)-ethyl)-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide, the code name: FLZ), a natural squamosamide derivative from a Chinese herb, has been shown to inhibit over-activated microglia and protect dopaminergic neurons in previous studies, but the mechanism remains unclear. In the present study, we further investigated the mechanism in lipopolysaccharide (LPS)-induced in vivo and in vitro PD models. FLZ treatment significantly improved the motor dysfunction of PD model rats induced by intra-nigral injection of LPS and this beneficial effect of FLZ attributed to the inhibition of microglial over-activation and the protection on dopaminergic neurons in the substantia nigra (SN). In vitro mechanistic study revealed that the inhibitive effect of FLZ on microglia was mediated by suppressing Src kinase related inflammatory signaling pathway activation and subsequent NF-κBp65 nuclear translocation, inhibiting nitric oxide (NO) and reactive oxygen species (ROS) production, decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. In conclusion, the present study supports that FLZ exerts neuroprotection against LPS-induced dopaminergic neurodegeneration through its anti-inflammatory effect, which is mediated by suppressing Src tyrosine kinase and the downstream inflammatory signaling pathway. Furthermore, this study defines a critical role of Src tyrosine kinase in neuroinflammation, and suggests that particular tyrosine kinase inhibition may be a potential anti-inflammatory approach for PD treatment.
神经炎症在帕金森病（PD）发病机制中的参与早已得到证实。过度活化的小胶质细胞释放大量促炎因子，损伤周围神经元并最终导致神经退行性变。抑制小胶质细胞过度活化可能是一种有前景的PD治疗策略。FLZ（化学名称：N-(2-(4-羟基苯基)乙基)-2-(2,5-二甲氧基苯基)-3-(3-甲氧基-4-羟基苯基)-丙烯酰胺，代号：FLZ），一种源自中草药的天然鳞状酰胺衍生物，在先前研究中已显示可抑制过度活化的小胶质细胞并保护多巴胺能神经元，但其机制仍不清楚。在本研究中，我们进一步在脂多糖（LPS）诱导的体内和体外PD模型中研究了其机制。FLZ治疗显著改善了经黑质内注射LPS诱导的PD模型大鼠的运动功能障碍，FLZ的这种有益作用归因于其对小胶质细胞过度活化的抑制以及对黑质中多巴胺能神经元的保护。体外机制研究表明，FLZ对小胶质细胞的抑制作用是通过抑制Src激酶相关炎症信号通路激活以及随后的NF-κBp65核转位，抑制一氧化氮（NO）和活性氧（ROS）生成，降低烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活化来介导的。总之，本研究支持FLZ通过其抗炎作用对LPS诱导的多巴胺能神经退行性变发挥神经保护作用，该抗炎作用由抑制Src酪氨酸激酶和下游炎症信号通路介导。此外，本研究确定了Src酪氨酸激酶在神经炎症中的关键作用，并表明特定酪氨酸激酶抑制可能是一种潜在的PD抗炎治疗方法。
