title: Silibinin Prevents Autophagic Cell Death upon Oxidative Stress in Cortical Neurons and Cerebral Ischemia-Reperfusion Injury.
abstract: Neuronal apoptosis and oxidative stress are involved in most of the neurodegenerative diseases, promoting neuron survival is critical for therapy. Silibinin (SLB), which is derived from the seeds of Silybinisus laborinum L., has been widely used as an antioxidant. Here we tested the neuroprotective effects of SLB and the involved molecular mechanisms. We demonstrated that SLB promoted neuron viability upon hydrogen peroxide (H2O2) challenge and reduced hypoxia/ischemia injury in the middle cerebral artery occlusion (MCAO) mouse model. SLB reversed the decreased level of procaspase-3 and balanced Bcl-2 and Bax expression upon H2O2 insult to inhibit cell apoptosis. Furthermore, SLB suppressed the activation of autophagy by decreasing microtubule-associated protein 1 light chain 3 (LC3-II) and Beclin-1 levels under oxidative stress accordingly. SLB phosphorylated protein kinase B (Akt-1) at Ser473 in a time- and dose-dependent manner. The inhibitor for phosphoinositide-3-kinase (PI3K) wortmannin abrogated SLB-induced phosphorylation of Akt-1 and mTOR, decreased the suppression of autophagy, and therefore abolished SLB-mediated neuroprotection. All the data suggested that SLB protected neurons by inhibiting both the mitochondrial and autophagic cell death pathways. This study opens new avenues for the use of SLB in treatment of central nervous system (CNS) diseases in which oxidative stress plays a major role in disease pathogenesis. Given that it occurs naturally with low toxicity and pleiotropic effects that benefit the nervous system, SLB acts potentially as a novel therapy for ischemic injury.
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Yu-Jiao
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Hui-Nan
authors.initials: HN
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Le
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Shui-Bing
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China. minggao@fmmu.edu.cn.
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China. yumeiwu@fmmu.edu.cn.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D012838:Silymarin; D000077385:Silybin; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Antioxidant; Apoptosis; Autophagy; Neuron; Oxidative stress; Silibinin; Survival