title: Baicalein protects against 6-OHDA-induced neurotoxicity through activation of Keap1/Nrf2/HO-1 and involving PKCα and PI3K/AKT signaling pathways.
abstract: Baicalein, one of the major flavonoids found in Scutellaria baicalensis Georgi, displays neuroprotective effects on experimental models of Parkinson's disease (PD) in vitro and in vivo. Although the antioxidative and/or anti-inflammatory activity of baicalein likely contributes to these neuroprotective effects, other modes of action remain largely uncharacterized. In the present study, baicalein pretreatment significantly prevented cells from 6-hydroxydopamine (6-OHDA)-induced damage by attenuating cellular apoptosis. However, post-treatment with baicalein did not show any restorative effect against 6-OHDA-induced cellular damage. We found that baicalein increased transcriptional factor NF-E2-related factor 2 (Nrf2)/hemo oxygenase 1(HO-1) protein expression and decreased Kelch-like ECH-associated protein 1 (Keap1) in a time- and concentration-dependent manner in PC12 cells. In addition, baicalein induced Nrf2 nuclear translocation and enhanced antioxidant response element (ARE) transcriptional activity, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, we demonstrated that cytoprotective effects of baicalein could be attenuated by Nrf2 siRNA transfection and the HO-1 inhibitor zinc protoporphyrin (Znpp) as well as the proteasome inhibitor MG132. Furthermore, PKCα and AKT protein phosphorylation were up-regulated by baicalein pretreatment, and selective inhibitors targeted to PKC, PI3K, and AKT could block the cytoprotective effects of baicalein. Taken together, our results indicate that baicalein prevented PC12 cells from 6-OHDA-induced oxidative damage via the activation of Keap1/Nrf2/HO-1, and it also involves the PKCα and PI3K/AKT signaling pathway. Ultimately, the neuroprotective effects of baicalein may endue baicalein as a promising candidate for the prevention of PD.
authors: State Key Laboratory of Quality Research in Chinese Medicine (University of Macau), Macao SAR, China.
authors: Zaijun
authors: Z
authors: Zhang
authors: Wei
authors: W
authors: Cui
authors: Guohui
authors: G
authors: Li
authors: Shuai
authors: S
authors: Yuan
authors: Daping
authors: D
authors: Xu
authors: Maggie P M
authors: MP
authors: Hoi
authors: Zhixiu
authors: Z
authors: Lin
authors: Juan
authors: J
authors: Dou
authors: Yifan
authors: Y
authors: Han
authors: Simon M Y
authors: SM
authors: Lee
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology; D019610:Cytoprotection; D044950:Flavanones / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D007976:Leupeptins / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D010766:Phosphorylation; D061988:Proteasome Inhibitors / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D044950:Flavanones; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D007976:Leupeptins; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D061988:Proteasome Inhibitors; D011506:Proteins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; C006680:baicalein; D016627:Oxidopamine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde