title: Silibinin activates AMP-activated protein kinase to protect neuronal cells from oxygen and glucose deprivation-re-oxygenation.
abstract: In this study, we explored the cytoprotective potential of silibinin against oxygen-glucose deprivation (OGD)-induced neuronal cell damages, and studied underling mechanisms. In vitro model of ischemic stroke was created by keeping neuronal cells (SH-SY5Y cells and primary mouse cortical neurons) in an OGD condition followed by re-oxygenation. Pre-treatment of silibinin significantly inhibited OGD/re-oxygenation-induced necrosis and apoptosis of neuronal cells. OGD/re-oxygenation-induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) reduction were also inhibited by silibinin. At the molecular level, silibinin treatment in SH-SY5Y cells and primary cortical neurons led to significant AMP-activated protein kinase (AMPK) signaling activation, detected by phosphorylations of AMPKα1, its upstream kinase liver kinase B1 (LKB1) and the downstream target acetyl-CoA Carboxylase (ACC). Pharmacological inhibition or genetic depletion of AMPK alleviated the neuroprotective ability of silibinin against OGD/re-oxygenation. Further, ROS scavenging ability by silibinin was abolished with AMPK inhibition or silencing. While A-769662, the AMPK activator, mimicked silibinin actions and suppressed ROS production and neuronal cell death following OGD/re-oxygenation. Together, these results show that silibinin-mediated neuroprotection requires activation of AMPK signaling.
authors.affiliation: Department of Anesthesiology, Shanghai International Medical Center, Shanghai 201318, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Ningxia Hospital of CAPF, Yinchuan City, Ningxia 750001, China.
authors.forename: Sheng-quan
authors.initials: SQ
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, Huashan Hospital Affiliated to Fudan University of Shanghai, Shanghai 201318, China. Electronic address: yafangshenmd@163.com.
authors.forename: Ya-fang
authors.initials: YF
authors.lastname: Shen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012838:Silymarin; D000077385:Silybin; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen
keywords: AMPK signaling; Oxygen and glucose deprivation/re-oxygenation; ROS and neuroprotection; Silibinin