Wruck C J, Claussen M, Fuhrmann G, Römer L, Schulz A, Pufe T, Waetzig V, Peipp M, Herdegen T, Götz M E
Institute of Pharmacology, University Clinic of Schleswig-Holstein, Kiel, Germany.
J Neural Transm Suppl. 2007(72):57-67. doi: 10.1007/978-3-211-73574-9_9.
Oxidative stress is central to neuronal damage in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In consequence, activation of the cerebral oxidative stress defence is considered as a promising strategy of therapeutic intervention. Here we demonstrate that the flavone luteolin confers neuroprotection against oxidative stress via activation of the nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor central to the maintenance of the cellular redox homeostasis. Luteolin protects rat neural PC12 and glial C6 cells from N-methyl-4-phenyl-pyridinium (MPP+) induced toxicity in vitro and effectively activates Nrf2 as shown by ARE-reporter gene assays. This protection critically depends on the activation of Nrf2 since downregulation of Nrf2 by shRNA completely abrogates the protection of luteolin in vitro. Furthermore, the neuroprotective effect of luteolin is abolished by the inhibition of the luteolin-induced ERK1/2-activation. Our results highlight the relevance of Nrf2 for neural cell survival conferred by flavones. In particular, we identified luteolin as a promising lead for the search of orally available, blood brain barrier permeable compounds to support the therapy of neurodegenerative disorders.
氧化应激是帕金森病和阿尔茨海默病等神经退行性疾病中神经元损伤的核心。因此，激活大脑氧化应激防御被认为是一种有前景的治疗干预策略。在此，我们证明黄酮木犀草素通过激活核因子红细胞2相关因子2（Nrf2）赋予对氧化应激的神经保护作用，Nrf2是维持细胞氧化还原稳态的关键转录因子。木犀草素在体外保护大鼠神经PC12细胞和神经胶质C6细胞免受N-甲基-4-苯基吡啶鎓（MPP+）诱导的毒性，并如ARE报告基因分析所示有效激活Nrf2。这种保护作用关键取决于Nrf2的激活，因为通过shRNA下调Nrf2完全消除了木犀草素在体外的保护作用。此外，木犀草素诱导的ERK1/2激活的抑制消除了木犀草素的神经保护作用。我们的结果突出了Nrf2对黄酮类化合物赋予神经细胞存活的相关性。特别是，我们确定木犀草素是寻找口服可用、可透过血脑屏障的化合物以支持神经退行性疾病治疗的一个有前景的先导物。
