诱导型一氧化氮合酶和缺氧缺血脑损伤

刘海婷; 母得志

doi:10.7499/j.issn.1008-8830.2014.09.022

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中国当代儿科杂志 ›› 2014, Vol. 16 ›› Issue (9) : 962-967. DOI: 10.7499/j.issn.1008-8830.2014.09.022

综述

诱导型一氧化氮合酶和缺氧缺血脑损伤

刘海婷^1,2, 母得志^1,2

作者信息 +

Inducible nitric oxide synthase and brain hypoxic-ischemic brain damage

LIU Hai-Ting^1,2, MU De-Zhi^1,2

Author information +

文章历史 +

摘要

缺氧缺血可导致严重的神经系统疾病，如脑卒中、新生儿缺氧缺血性脑病。诱导型一氧化氮合酶在缺氧、缺血过程中被诱导表达，产生过量一氧化氮，导致神经系统的炎症反应及神经元死亡，加重神经损伤。抑制诱导型一氧化氮合酶表达在体内体外实验及临床应用中显示了一定的神经保护作用。该文综述了诱导型一氧化氮合酶在中枢神经系统中的表达及与缺氧缺血脑损伤的相关性，展望了诱导型一氧化氮合酶抑制剂作为缺氧缺血脑损伤治疗策略的前景。

Abstract

Brain hypoxia-ischemia has been considered as critical factors in many human central nervous system diseases, including stroke and neonatal hypoxic-ischemic encephalopathy. In brain hypoxia-ischemia processes, inducible NO synthase（iNOS) is induced to produce excessive nitric oxide（NO) which leads to cascade reactions of inflammation and neuronal death, deteriorating primary brain injury. Inhibiting iNOS expression has opened new perspectives in the treatment of brain hypoxia-ischemia because iNOS inhibitor has been shown as a potent therapeutic agent. This reviews focus on recent research achievements regarding the relationship between iNOS and ischemic-hypoxic brain damage and the perspective of using iNOS inhibitors as therapeutic strategies for brain ischemic-hypoxic brain damage.

导出引用

刘海婷, 母得志. 诱导型一氧化氮合酶和缺氧缺血脑损伤[J]. 中国当代儿科杂志. 2014, 16(9): 962-967 https://doi.org/10.7499/j.issn.1008-8830.2014.09.022

LIU Hai-Ting, MU De-Zhi. Inducible nitric oxide synthase and brain hypoxic-ischemic brain damage[J]. Chinese Journal of Contemporary Pediatrics. 2014, 16(9): 962-967 https://doi.org/10.7499/j.issn.1008-8830.2014.09.022

参考文献

[1] Iadecola C, Zhang F, Xu S, et al.Inducible nitric oxide synthase gene expression in brain following cerebral ischemia[J].J Cereb Blood Flow Metab, 1995, 15(3): 378-384.
[2] Forstermann U, Sessa WC.Nitric oxide synthases: regulation and function[J].Eur Heart J, 2012, 33(7): 829-837.
[3] Qi SH, Hao LY, Yue J, et al.Exogenous nitric oxide negatively regulates the S-nitrosylation p38 mitogen-activated protein kinase activation during cerebral ischaemia and reperfusion[J].Neuropathol Appl Neurobiol, 2013, 39(3): 284-297.
[4] Kleinert H, Pautz A, Linker K, et al.Regulation of the expression of inducible nitric oxide synthase[J].Eur J Pharmacol, 2004, 500(1-3): 255-266.
[5] Robinson MA, Baumgardner JE, Otto CM.Oxygen-dependent regulation of nitric oxide production by inducible nitric oxide synthase[J].Free Radic Biol Med, 2011, 51(11): 1952-1965.
[6] Zhang L, Liu Q, Yuan X, et al.Requirement of heat shock protein 70 for inducible nitric oxide synthase induction[J].Cell Signal, 2013, 25(5): 1310-1317.
[7] Badamtseren B, Odkhuu E, Koide N, et al.Thalidomide inhibits interferon-gamma-mediated nitric oxide production in mouse vascular endothelial cells[J].Cell Immunol, 2011, 270(1): 19-24.
[8] Saha RN, Pahan K.Signals for the induction of nitric oxide synthase in astrocytes[J].Neurochem Int, 2006, 49(2): 154-163.
[9] Ko HM, Kim SY, Joo SH, et al.Synergistic activation of lipopolysaccharide-stimulated glial cells by propofol[J].Biochem Biophys Res Commun, 2013, 438(2): 420-426.
[10] Xu C, Ren G, Cao G, et al.miR-155 regulates immune modulatory properties of mesenchymal stem cells by targeting TAK1-binding protein 2[J].J Biol Chem, 2013, 288(16): 11074-11079.
[11] Perske C, Lahat N, Sheffy Levin S, et al.Loss of inducible nitric oxide synthase expression in the mouse renal cell carcinoma cell line RENCA is mediated by microRNA miR-146a[J].Am J Pathol, 2010, 177(4): 2046-2054.
[12] Zhou M, Wang CM, Yang WL, et al.Microglial CD14 activated by iNOS contributes to neuroinflammation in cerebral ischemia[J].Brain Res, 2013, 1506: 105-114.
[13] Zhang L, Dong LY, Li YJ, et al.The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor[J].J Neuroinflammation, 2012(9): 211.
[14] Bauer V, Sotnikova R.Nitric oxide--the endothelium-derived relaxing factor and its role in endothelial functions[J].Gen Physiol Biophys, 2010, 29(4): 319-340.
[15] Yu L, Derrick M, Ji H, et al.Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole[J].Dev Neurosci, 2011, 33(3-4): 312-319.
[16] Zeng XW, Li MW, Pan J, et al.Activation of c-Jun N-terminal kinase 1/2 regulated by nitric oxide is associated with neuronal survival in hippocampal neurons in a rat model of ischemia[J].Chin Med J（Engl), 2011, 124(20): 3367-3372.
[17] Ono K, Suzuki H, Sawada M.Delayed neural damage is induced by iNOS-expressing microglia in a brain injury model[J].Neurosci Lett, 2010, 473(2): 146-150.
[18] Benavides GA, Liang Q, Dodson M, et al.Inhibition of autophagy and glycolysis by nitric oxide during hypoxia-reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons[J].Free Radic Biol Med, 2013, 65C:1215-1228.
[19] Khovryakov AV, Podrezova EP, Kruglyakov PP, et al.Involvement of the NO synthase system in stress-mediated brain reactions[J].Neurosci Behav Physiol, 2010, 40(3): 333-337.
[20] Martinez-Ruiz A, Cadenas S, Lamas S.Nitric oxide signaling:classical, less classical, and nonclassical mechanisms[J].Free Radic Biol Med, 2011, 51(1): 17-29.
[21] ArunaDevi R, Ramteke VD, Kumar S, et al.Neuroprotective effect of s-methylisothiourea in transient focal cerebral ischemia in rat[J].Nitric Oxide, 2010, 22(1): 1-10.
[22] Chang CC, Wang YH, Chern CM, et al.Prodigiosin inhibits gp91(phox) and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia[J].Toxicol Appl Pharmacol, 2011, 257(1): 137-147.
[23] Shi ZQ, Sunico CR, McKercher SR, et al.S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke[J].Proc Natl Acad Sci U S A, 2013, 110(8):3137-3142.
[24] Sen N, Hara MR, Kornberg MD, et al.Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis[J].Nat Cell Biol, 2008, 10(7): 866-873.
[25] Mishra OP, Randis T, Ashraf QM, et al.Hypoxia-induced Bax and Bcl-2 protein expression, caspase-9 activation, DNA fragmentation, and lipid peroxidation in mitochondria of the cerebral cortex of newborn piglets: the role of nitric oxide[J].Neuroscience, 2006, 141(3): 1339-1349.
[26] Mizushima N, Levine B, Cuervo AM,et al.Autophagy fights disease through cellular self-digestion[J].Nature, 2008,451(7182): 1069-1075.
[27] Iadecola C, Zhang F, Casey R, et al.Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene[J].J Neurosci, 1997,17(23): 9157-9164.
[28] Tuna M, Yilmaz DM, Erman T, et al.Effect of neutralization of rat interleukin 6 bioactivity on inducible nitric oxide synthase up-regulation and cerebral ischemic damage[J].Neurol Res,2009, 31(7): 714-720.
[29] Shao L, Guo Z, Geller DA.Transcriptional suppression of cytokine-induced iNOS gene expression by IL-13 through IRF-1/ISRE signaling[J].Biochem Biophys Res Commun, 2007,362(3): 582-586.
[30] Leppanen T, Korhonen R, Laavola M, et al.Down-regulation of protein kinase Cdelta inhibits inducible nitric oxide synthase expression through IRF1[J].PLoS One, 2013, 8(1): e52741.
[31] Li H, Liu B, Huang J, et al.Insulin inhibits lipopolysaccharide-induced nitric oxide synthase expression in rat primary astrocytes[J].Brain Res, 2013, 1506: 1-11.
[32] Harari OA, Liao JK.NF-kappaB and innate immunity in ischemic stroke[J].Ann N Y Acad Sci, 2010, 1207: 32-40.
[33] Mi Z, Rapisarda A, Taylor L, et al.Synergystic induction of HIF-1alpha transcriptional activity by hypoxia and lipopolysaccharide in macrophages[J].Cell Cycle, 2008, 7(2):232-241.
[34] Chern CM, Liou KT, Wang YH, et al.Andrographolide inhibits PI3K/AKT-dependent NOX2 and iNOS expression protecting mice against hypoxia/ischemia-induced oxidative brain injury[J].Planta Med 2011, 77(15): 1669-1679.
[35] Kunz A, Abe T, Hochrainer K, et al.Nuclear factor-kappaB activation and postischemic inflammation are suppressed in CD36-null mice after middle cerebral artery occlusion[J].J Neurosci, 2008, 28(7): 1649-1658.
[36] Brown CM, Dela Cruz CD, Yang E, et al.Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury[J].Exp Neurol, 2008, 210(2):782-787.
[37] Park EM, Cho S, Frys KA, et al.Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury[J].J Cereb Blood Flow Metab, 2006, 26(3): 392-401.
[38] Lopez-Arenas E, Mackay-Sim A, Bacigalupo J, et al.Leukaemia inhibitory factor stimulates proliferation of olfactory neuronal progenitors via inducible nitric oxide synthase[J].PLoS One,2012, 7(9): e45018.
[39] Bechade C, Pascual O, Triller A, Bessis A.Nitric oxide regulates astrocyte maturation in the hippocampus: involvement of NOS2[J].Mol Cell Neurosci, 2011, 46(4): 762-769.
[40] Corsani L, Bizzoco E, Pedata F, et al.Inducible nitric oxide synthase appears and is co-expressed with the neuronal isoform in interneurons of the rat hippocampus after transient ischemia induced by middle cerebral artery occlusion[J].Exp Neurol,2008, 211(2): 433-440.
[41] Luo CX, Zhu XJ, Zhou QG, et al.Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression[J].J Neurochem, 2007, 103(5): 1872-1882.
[42] Shen L, Zhang J.NMDA receptor and iNOS are involved in the effects of ginsenoside Rg1 on hippocampal neurogenesis in ischemic gerbils[J].Neurol Res, 2007, 29(3): 270-273.
[43] Li QF, Zhu YS, Jiang H.Isoflurane preconditioning activates HIF-1alpha, iNOS and Erk1/2 and protects against oxygen-glucose deprivation neuronal injury[J].Brain Res 2008, 1245:26-35.
[44] Fang Li Q, Xu H, Sun Y, et al.Induction of inducible nitric oxide synthase by isoflurane post-conditioning via hypoxia inducible factor-1alpha during tolerance against ischemic neuronal injury[J].Brain Res, 2012, 1451: 1-9.
[45] Kawano T, Kunz A, Abe T, et al.iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite[J].J Cereb Blood Flow, Metab, 2007,27(8): 1453-1462.

基金

国家自然科学基金（81330016，31171020，81270724，81172174）；教育部科研基金（13037，20110181130002，IRT0935）；国家科技部基金（2012BAI04B04）；国家临床重点专科（儿科新生儿专业）建议项目（1311200003303）；四川省科技厅科技支撑项目（2012SZ0150）资助。