Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway.
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.
Wruck
C J
CJ
Institute of Pharmacology, University Clinic of Schleswig-Holstein, Kiel, Germany.
Claussen
M
M
Fuhrmann
G
G
Römer
L
L
Schulz
A
A
Pufe
T
T
Waetzig
V
V
Peipp
M
M
Herdegen
T
T
Götz
M E
ME
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics*; D006540:Herbicides / Q000633:toxicity*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D047311:Luteolin / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D011506:Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; D005419:Flavonoids; D006540:Herbicides; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011506:Proteins; D034741:RNA, Small Interfering; D047311:Luteolin; D015655:1-Methyl-4-phenylpyridinium