title: Induction of Pi form of glutathione S-transferase by carnosic acid is mediated through PI3K/Akt/NF-κB pathway and protects against neurotoxicity.
abstract: Carnosic acid (CA), a diterpene found in the rosemary (Rosmarinus officinalis), has been reported to have a neuroprotective effect. Glutathione S-transferase (GST) P (GSTP) is a phase II detoxifying enzyme that provides a neuroprotective effect. The aim of this study was to explore whether the neuroprotective effect of CA is via an upregulation of GSTP expression and the possible signaling pathways involved. SH-SY5Y cells were pretreated with 1 μM CA followed by treatment with 100 μM 6-hydroxydopamine (6-OHDA). Both immunoblotting and enzyme activity results show that CA also induced protein expression and enzyme activity of GSTP. Moreover, CA significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt, the nuclear translocation of p65, but not mitogen-activated protein kinases (p < 0.05). Pretreatment with LY294002 (a PI3K/Akt inhibitor) suppressed the CA-induced phosphorylation of IκB kinase (IKK) and IκBα, p65 nuclear translocation, and nuclear factor-kappa B (NF-κB)-DNA binding activity as well as GSTP protein expression. Furthermore, CA attenuated 6-OHDA-induced caspase 3 activation, and cell death was reversed by GSTP siRNA or LY294002 treatment. Additionally, male Wistar rats with lesions induced by 6-OHDA treatment in the right striatum responded to treatment with CA, which significantly reversed the reduction in GSTP protein expression that resulted from lesioning. We suggest that CA prevents 6-OHDA-induced apoptosis through an increase in GSTP expression via activation of the PI3K/Akt/NF-κB pathway. Therefore, CA may be a promising candidate for use in the prevention of Parkinson's disease.
authors.affiliation: Department of Nutrition, China Medical University , 40402 Taichung, Taiwan.
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Lin
authors.forename: Jing-Hsien
authors.initials: JH
authors.lastname: Chen
authors.forename: Ru-Huei
authors.initials: RH
authors.lastname: Fu
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
mesh_terms: D045784:Abietanes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D016627:Oxidopamine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D045784:Abietanes; D051549:Glutathione S-Transferase pi; D016328:NF-kappa B; D018696:Neuroprotective Agents; D016627:Oxidopamine; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; C018381:salvin