title: SVCT2, a potential therapeutic target, protects against oxidative stress during ethanol-induced neurotoxicity via JNK/p38 MAPKs, NF-κB and miRNA125a-5p.
abstract: Sodium vitamin C transporter 2 (SVCT2) plays a key role in transporting ascorbic acid (AA), an important intracellular antioxidant, into neurons. It is well known that ethanol (EtOH) abuse causes significant neurodegeneration, as well as endogenous AA release in certain encephalic regions. Here, we identified that SVCT2 forms part of a self-defense mechanism that protects against oxidative stress in binge drinking rats, and SVCT2 levels are correlated with antioxidants and neuronal injury. Four days of binge drinking led to massive neuron degeneration in prefrontal cortex (PFC), accompanied by increased levels of 4-hydroxynonenal (4-HNE)-adducted proteins and SVCT2 expression, as well as dramatic changes in AA levels in rat brain. AA levels were decreased in PFC and increased in cerebrospinal fluid (CSF) after binge drinking, but returned to normal on the 7th day following EtOH withdrawal. These processes were further evaluated in primary cortical neurons exposed to 100mM EtOH in vitro. Neurons transfected with SVCT2 siRNA were more susceptible than controls to certain aspects of EtOH-induced injury, including cell death, dendrite damage and increased oxidative stress. EtOH-induced up-regulation of SVCT2 was associated with activation of JNK and p38 MAPKs and the NF-κB pathway. More importantly, miRNA-125a-5p was down-regulated in PFC of 4-day binge drinking rats and negatively regulated protein expression during EtOH-induced neuronal injury. MiR-125a-5p over-expression attenuated intracellular AA levels, promoted cell death and suppressed the EtOH-induced up-regulation of p38 MAPK and SVCT2, which suggested that miR-125a-5p plays an important role in SVCT2 function in EtOH-induced neuronal injury. We speculate that SVCT2, possibly regulated by JNK/p38 MAPKs, NF-κB signaling and miR-125a-5p, has a neuroprotective effect against EtOH-induced oxidative stress. Promotion of SVCT2 expression or stimulation of SVCT2 activity may be a promising therapeutic strategy for the prevention of EtOH-associated neurodegeneration.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Department of Pharmacology, Qiqihar Medical University, Qiqihar 161006, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: yangjingyu2006@gmail.com.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: wucf@syphu.edu.cn.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism; D063425:Binge Drinking / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D035683:MicroRNAs; D016328:NF-kappa B; D034741:RNA, Small Interfering; C555167:Slc23a2 protein, rat; D060347:Sodium-Coupled Vitamin C Transporters; D000431:Ethanol; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C027576:4-hydroxy-2-nonenal; D001205:Ascorbic Acid
keywords: Ascorbic acid; Ethanol; MiR-125a-5p; Neurodegeneration; Oxidative stress; SVCT2