title: Inhibition of JNK by pi class of glutathione S-transferase through PKA/CREB pathway is associated with carnosic acid protection against 6-hydroxydopamine-induced apoptosis.
abstract: Pi class of glutathione S-transferase (GST) is known to suppress c-Jun N-terminal kinase (JNK)-related apoptosis through protein-protein interactions. Moreover, signaling by PKA/cAMP response element binding protein (CREB) is necessary for GSTP up-regulation. This study explored whether carnosic acid (CA) from rosemary prevents 6-hydroxydopamine (6-OHDA)-induced neurotoxicity by inhibition of JNK through GSTP via PKA/CREB signaling. Results indicated that the GSTP protein was increased in SH-SY5Y cells treated with CA for 18 and 24 h. However, CA had no significant effect on alpha or mu class of GST. Treatment of CA increased the induction of p-PKAα, nuclear p-CREB, and CRE-DNA binding activity. These effects of CA were attenuated in cells pretreated with the PKA inhibitor H89. CA pretreatment suppressed 6-OHDA-induced apoptosis by inhibition of JNK phosphorylation, poly(ADP)-ribose polymerase cleavage, and nuclear condensation. Pretreatment with H89 and GSTP siRNA attenuated the ability of CA to reverse 6-OHDA-induced apoptosis. By use of immunoprecipitation with JNK antibody to examine the interaction of GSTP-JNK with CA, we showed that CA pretreatment increased the immunoprecipitation of GSTP after 6-OHDA treatment, which suggests that CA promoted the interaction between GSTP and JNK.
  
  
  CONCLUSIONS
  CA prevents 6-OHDA-induced apoptosis via inhibition of JNK by GSTP through the PKA/CREB pathway.
authors.affiliation: Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ru-Huei
authors.initials: RH
authors.lastname: Fu
authors.affiliation: Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Ruey-Hwang
authors.initials: RH
authors.lastname: Chou
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Jing-Hsien
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan.
authors.forename: Chi-Rei
authors.initials: CR
authors.lastname: Wu
authors.affiliation: Department of Medicinal Botanicals and Health Care, Dayeh University, Changhua, Taiwan.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Chang
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan. Electronic address: cwtsai@mail.cmu.edu.tw.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D045784:Abietanes; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D013449:Sulfonamides; D016627:Oxidopamine; D051549:Glutathione S-Transferase pi; D017868:Cyclic AMP-Dependent Protein Kinases; D048670:MAP Kinase Kinase 4; C018381:salvin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Carnosic acid; Pi class of glutathione; Protein kinase A pathway; S-transferase; SH-SY5Y cells; c-Jun N-Terminal kinase