title: Saikosaponin D acts against corticosterone-induced apoptosis via regulation of mitochondrial GR translocation and a GR-dependent pathway.
abstract: Saikosaponin D is an agonist of the glucocorticoid receptor (GR), and our preliminary study showed that it possesses neuroprotective effects in corticosterone-treated PC12 cells. However, further proof is required, and the molecular mechanisms of this neuroprotection remain unclear. This study sought to further examine the cytoprotective efficiency and potential mechanisms of action of Saikosaponin D in corticosterone-treated PC12 cells. The cells were treated with 250 μM corticosterone in the absence or presence of Saikosaponin D for 24 h; cell viability was then determined, and Hoechst 33342/propidium iodide (PI) and annexin/PI double staining, and TUNEL staining were performed. Next, mPTP, MMP, [Ca(2+)]i, translocation of the GR to the nucleus and Western blot analyses for caspase-3, caspase-9, cytochrome C, GR, GILZ, SGK-1, NF-Κb (P65), IκB-α, Bad, Akt, Hsp90 and HDAC-6 were investigated. The neuroprotective effects of Saikosaponin D were further confirmed by Hoechst 33342/PI, annexin/PI and TUNEL staining assays. These additional data suggested that Saikosaponin D partially reversed the physiological changes induced by corticosterone by inhibiting the translocation of the GR to the mitochondria, restoring mitochondrial function, down-regulating the expression of pro-apoptotic-related signalling events and up-regulating anti-apoptotic-related signalling events. These findings suggest that SSD exhibited its anti-apoptotic effects via differential regulation of mitochondrial and nuclear GR translocation, partial reversal of mitochondrial dysfunction, inhibition of the mitochondrial apoptotic pathway, and selective activation of the GR-dependent survival pathway.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China.
authors.forename: Zong-Yang
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China.
authors.forename: Yu-Mao
authors.initials: YM
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China.
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Shen
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China.
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China. Electronic address: rlpan@implad.ac.cn.
authors.forename: Rui-Le
authors.initials: RL
authors.lastname: Pan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016716:PC12 Cells; D011419:Propidium; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D017304:Annexin A5; D000893:Anti-Inflammatory Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011965:Receptors, Glucocorticoid; D012503:Saponins; D011419:Propidium; D009828:Oleanolic Acid; D002118:Calcium; C025759:saikosaponin D; D003345:Corticosterone
keywords: Corticosterone; Glucocorticoid receptor; Mitochondria; Neuroprotection; Saikosaponin D