NR4A1 enhances neural survival following oxygen and glucose deprivation: An in vitro study

  • Guodong Xiao
    Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, China
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  • Tao Sun
    Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, 210002, China
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  • Cheng Songming
    Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, 210002, China
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  • Yongjun Cao
    Corresponding author at: Department of Neurology, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Rd, Suzhou, Jiangsu Province, 215004, China. Tel.: +86 15052253917.
    Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, China
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      A worldwide epidemic of stroke is exacting a huge level of patient suffering and social cost. The ischemia damage to neural cells and the associated permanent neural function loss are central to the pathophysiology of stroke.
      In the current study, we were endeavored to identify NR4A1, an orphan nuclear receptor as a novel protector for neural cells in an in vitro neural ischemia model. Our results showed that oxygen and glucose deprivation (OGD) dramatically induced primary culture neural cell apoptosis and NR4A1 expression at both protein and mRNA level. Furthermore, hyperexpression or knock-down of NR4A1 significantly ameliorated or exacerbated OGD induced neural damage as manifested by decreased or increased apoptotic rates and key apoptotic protein expression respectively. As part of effort to identify the underlying mechanism, we also found that survivin is highly inducible following OGD and is required for NR4A1 action in this scenario.
      Our data seemed to be logical extensions of previous observations showing that NR4As are highly inducible following focal cerebral ischemia. Of note, our results also demonstrated that NR4A1 induction in this scenario may be functionally important as well and targeting NR4A1 protein can be intriguing as part of the effort to develop novel therapeutic strategies for neural protection after stroke.


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        • Mathers C.D.
        • Boerma T.
        • Ma Fat D.
        Global and regional causes of death.
        Br Med Bull. 2009; 92 ([PubMed PMID: 19776034. Epub 2009/09/25. eng]): 7-32
        • Rosamond W.
        • Flegal K.
        • Furie K.
        • Go A.
        • Greenlund K.
        • Haase N.
        • et al.
        Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
        Circulation. Jan 29 2008; 117 ([PubMed PMID: 18086926. Epub 2007/12/19. eng]): e25-e146
        • Li C.
        • Yan Z.
        • Yang J.
        • Chen H.
        • Li H.
        • Jiang Y.
        • et al.
        Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats.
        Neurochem Int. Feb 2010; 56 ([PubMed PMID: 20026214. Epub 2009/12/23. eng]): 495-500
        • Yeung F.
        • Hoberg J.E.
        • Ramsey C.S.
        • Keller M.D.
        • Jones D.R.
        • Frye R.A.
        • et al.
        Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
        EMBO J. Jun 16 2004; 23 ([PubMed PMID: 15152190. Pubmed Central PMCID: 423286. Epub 2004/05/21. eng]): 2369-2380
        • Volakakis N.
        • Kadkhodaei B.
        • Joodmardi E.
        • Wallis K.
        • Panman L.
        • Silvaggi J.
        • et al.
        NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection.
        Proc Natl Acad Sci U S A. Jul 6 2010; 107 ([PubMed PMID: 20566846. Pubmed Central PMCID: 2901488. Epub 2010/06/23. eng]): 12317-12322
        • Pols T.W.
        • de Vries C.J.
        A shining future for NR4A nuclear receptors in DNA repair.
        Pigment Cell Melanoma Res. Jun 2008; 21 ([PubMed PMID: 18476908. Epub 2008/05/15. eng]): 342-343
        • Bonta P.I.
        • Pols T.W.
        • de Vries C.J.
        NR4A nuclear receptors in atherosclerosis and vein–graft disease.
        Trends Cardiovasc Med. Apr 2007; 17 ([PubMed PMID: 17418373. Epub 2007/04/10. eng]): 105-111
        • Li Q.X.
        • Ke N.
        • Sundaram R.
        • Wong-Staal F.
        NR4A1, 2, 3—an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis.
        Histol Histopathol. May 2006; 21 ([PubMed PMID: 16493583. Epub 2006/02/24. eng]): 533-540
        • Fu Y.
        • Luo L.
        • Luo N.
        • Zhu X.
        • Garvey W.T.
        NR4A orphan nuclear receptors modulate insulin action and the glucose transport system: potential role in insulin resistance.
        J Biol Chem. Oct 26 2007; 282 ([PubMed PMID: 17785466. Epub 2007/09/06. eng]): 31525-31533
        • Chao L.C.
        • Zhang Z.
        • Pei L.
        • Saito T.
        • Tontonoz P.
        • Pilch P.F.
        Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle.
        Mol Endocrinol. Sep 2007; 21 ([PubMed PMID: 17550977. Pubmed Central PMCID: 2602962. Epub 2007/06/07. eng]): 2152-2163
        • Johansson I.M.
        • Wester P.
        • Hakova M.
        • Gu W.
        • Seckl J.R.
        • Olsson T.
        Early and delayed induction of immediate early gene expression in a novel focal cerebral ischemia model in the rat.
        Eur J Neurosci. Oct 2000; 12 ([PubMed PMID: 11029632. Epub 2000/10/13. eng]): 3615-3625
        • Gallo V.
        • Suergiu R.
        • Giovannini C.
        • Levi G.
        Glutamate receptor subtypes in cultured cerebellar neurons: modulation of glutamate and gamma-aminobutyric acid release.
        J Neurochem. Dec 1987; 49 ([PubMed PMID: 2890714. Epub 1987/12/01. eng]): 1801-1809
        • Malik Y.S.
        • Sheikh M.A.
        • Zhu X.
        Doxycycline can stimulate cytoprotection in neural stem cells with oxygen-glucose deprivation-reoxygenation injury: a potential approach to enhance effectiveness of cell transplantation therapy.
        Biochem Biophys Res Commun. Mar 8 2013; 432: 355-358
        • Dennis S.H.
        • Jaafari N.
        • Cimarosti H.
        • Hanley J.G.
        • Henley J.M.
        • Mellor J.R.
        Oxygen/glucose deprivation induces a reduction in synaptic AMPA receptors on hippocampal CA3 neurons mediated by mGluR1 and adenosine A3 receptors.
        J Neurosci. Aug 17 2011; 31 ([PubMed PMID: 21849555. Pubmed Central PMCID: 3160741]): 11941-11952
        • Li H.
        • Hu J.
        • Ma L.
        • Yuan Z.
        • Wang Y.
        • Wang X.
        • et al.
        Comprehensive study of baicalin down-regulating NOD2 receptor expression of neurons with oxygen–glucose deprivation in vitro and cerebral ischemia–reperfusion in vivo.
        Eur J Pharmacol. Dec 15 2010; 649: 92-99
        • Tang Z.
        • Sun X.
        • Huo G.
        • Xie Y.
        • Shi Q.
        • Chen S.
        • et al.
        Protective effects of erythropoietin on astrocytic swelling after oxygen–glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway.
        Neuropharmacology. Apr 2013; 67: 8-15
        • Dyker A.G.
        • Lees K.R.
        Duration of neuroprotective treatment for ischemic stroke.
        Stroke. Feb 1998; 29 ([PubMed PMID: 9472902. Epub 1998/02/24. eng]): 535-542
        • Kuan C.Y.
        • Whitmarsh A.J.
        • Yang D.D.
        • Liao G.
        • Schloemer A.J.
        • Dong C.
        • et al.
        A critical role of neural-specific JNK3 for ischemic apoptosis.
        Proc Natl Acad Sci U S A. Dec 9 2003; 100 ([PubMed PMID: 14657393. Pubmed Central PMCID: 299947]): 15184-15189
        • Zhang P.
        • Li W.
        • Li L.
        • Wang N.
        • Li X.
        • Gao M.
        • et al.
        Treatment with edaravone attenuates ischemic brain injury and inhibits neurogenesis in the subventricular zone of adult rats after focal cerebral ischemia and reperfusion injury.
        Neuroscience. Jan 10 2012; 201: 297-306
        • Gao Y.
        • Gao G.
        • Long C.
        • Han S.
        • Zu P.
        • Fang L.
        • et al.
        Enhanced phosphorylation of cyclic AMP response element binding protein in the brain of mice following repetitive hypoxic exposure.
        Biochem Biophys Res Commun. Feb 10 2006; 340: 661-667
        • Maxwell M.A.
        • Muscat G.E.
        The NR4A subgroup: immediate early response genes with pleiotropic physiological roles.
        Nucl Recept Signal. 2006; 4 ([PubMed PMID: 16604165. Pubmed Central PMCID: 1402209. Epub 2006/04/11. eng]): e002
        • Dahlqvist P.
        • Ronnback A.
        • Risedal A.
        • Nergardh R.
        • Johansson I.M.
        • Seckl J.R.
        • et al.
        Effects of postischemic environment on transcription factor and serotonin receptor expression after permanent focal cortical ischemia in rats.
        Neuroscience. 2003; 119 ([PubMed PMID: 12809685. Epub 2003/06/18. eng]): 643-652
        • Fu M.
        • Sun T.
        • Bookout A.L.
        • Downes M.
        • Yu R.T.
        • Evans R.M.
        • et al.
        A nuclear receptor atlas: 3T3-L1 adipogenesis.
        Mol Endocrinol. Oct 2005; 19 ([PubMed PMID: 16051663. Epub 2005/07/30. eng]): 2437-2450
        • Werme M.
        • Ringholm A.
        • Olson L.
        • Brene S.
        Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine.
        Brain Res. Apr 28 2000; 863 ([PubMed PMID: 10773199. Epub 2000/04/25. eng]): 112-119
        • Werme M.
        • Olson L.
        • Brene S.
        NGFI-B and nor1 mRNAs are upregulated in brain reward pathways by drugs of abuse: different effects in Fischer and Lewis rats.
        Brain Res Mol Brain Res. Mar 10 2000; 76 ([PubMed PMID: 10719211. Epub 2000/03/17. eng]): 18-24
        • Tamm I.
        • Wang Y.
        • Sausville E.
        • Scudiero D.A.
        • Vigna N.
        • Oltersdorf T.
        • et al.
        IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs.
        Cancer Res. Dec 1 1998; 58: 5315-5320
        • Sah N.K.
        • Khan Z.
        • Khan G.J.
        • Bisen P.S.
        Structural, functional and therapeutic biology of survivin.
        Cancer Lett. Dec 8 2006; 244: 164-171