RGD Reference Report - SVCT2, a potential therapeutic target, protects against oxidative stress during ethanol-induced neurotoxicity via JNK/p38 MAPKs, NF-κB and miRNA125a-5p. - Rat Genome Database

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SVCT2, a potential therapeutic target, protects against oxidative stress during ethanol-induced neurotoxicity via JNK/p38 MAPKs, NF-κB and miRNA125a-5p.

Authors: Tian, Hua  Ye, Xiaoxia  Hou, Xiaojie  Yang, Xiaowei  Yang, Jingyu  Wu, Chunfu 
Citation: Tian H, etal., Free Radic Biol Med. 2016 Jul;96:362-73. doi: 10.1016/j.freeradbiomed.2016.03.039. Epub 2016 Apr 13.
RGD ID: 26884454
Pubmed: PMID:27085842   (View Abstract at PubMed)
DOI: DOI:10.1016/j.freeradbiomed.2016.03.039   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Binge Drinking  ISOMir125a (Rattus norvegicus)26884454; 26884454RNA:decreased expression:neuronRGD 
Binge Drinking  IEP 26884454RNA:decreased expression:neuronRGD 
Binge Drinking  ISOSlc23a2 (Rattus norvegicus)26884454; 26884454 RGD 
Binge Drinking  IEP 26884454 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to ethanol  IEP 26884454 RGD 
L-ascorbic acid metabolic process  IDA 26884454 RGD 
negative regulation of cellular process  IMP 26884454cortical neuron deathRGD 
positive regulation of cellular process  IMP 26884454cortical neuron deathRGD 
positive regulation of dendrite extension  IMP 26884454 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mir125a  (microRNA 125a)
Slc23a2  (solute carrier family 23 member 2)

Genes (Mus musculus)
Mir125a  (microRNA 125a)
Slc23a2  (solute carrier family 23 (nucleobase transporters), member 2)

Genes (Homo sapiens)
MIR125A  (microRNA 125a)
SLC23A2  (solute carrier family 23 member 2)


Additional Information