锌离子在脑缺血中作用的研究进展

doi:10.3969/j.issn.1006-7795.2013.01.014

摘要/Abstract

摘要：

近期研究表明,锌离子是介导脑缺血损伤的一种重要离子。缺血时,大量的锌离子从突触末端释放出来,聚集于突触后神经元内。缺血时产生的氧化应激和酸中毒也促使锌离子从胞内锌结合位点如金属硫蛋白释放。急剧的胞内锌超载可引起严重的线粒体功能障碍及活性氧簇产生,继而引起细胞坏死,而轻度的胞内锌超载则可能放大凋亡通路,导致细胞凋亡。深入研究锌离子在缺血损伤中的作用有可能为缺血性脑卒中的防治提供新策略。

关键词: 锌离子, 脑缺血, 脑损伤

Abstract:

Recent reports have indicated that zinc ion (Zn²⁺) plays an important role in the mechanism of brain injury following cerebral ischemia. Large amount of Zn²⁺ is released from synaptic vesicles and accumulates in postsynaptic neurons following cerebral ischemia. In addition, oxidative stress and acidosis, both of which occur prominently in ischemia, can induce Zn²⁺ release from zinc-ligands such as metallothionein proteins. Intense cytosolic Zn²⁺ overloads can promote pronounced mitochondrial dysfunction and reactive oxygen species generation to trigger necrosis, whereas milder cytosolic Zn²⁺ loads may augment apoptotic pathways. Further investigation of the contribution of Zn²⁺ to the mechanism of brain injury following cerebral ischemia will likely provide new preventive and therapeutic strategies for ischemic stroke.

Key words: Zn²⁺, cerebral ischemia, brain injury

中图分类号:

R743.31

李森, 刘克建, 赵咏梅. 锌离子在脑缺血中作用的研究进展[J]. 首都医科大学学报, 2013, 34(1): 75-79.

LI Sen, LIU Kejian, ZHAO Yongmei. Recent progress in studies on the role of Zn²⁺ in cerebral ischemia[J]. Journal of Capital Medical University, 2013, 34(1): 75-79.

参考文献

[1] Sensi S L, Paoletti P, Bush A I, et al. Zinc in the physiology and pathology of the CNS [J]. Nat Rev Neurosci, 2009, 10(11):780-791.

[2] Bitanihirwe B K, Cunningham M G. Zinc: the brain’s dark horse [J]. Synapse, 2009, 63(11):1029-1049.

[3] Ohana E, Segal D, Palty R, et al. A sodium zinc exchange mechanism is mediating extrusion of zinc in mammalian cells [J]. J Biol Chem, 2004, 279(6):4278-4284.

[4] Aguilar-Alonso P, Martinez-Fong D, Pazos-Salazar N G, et al. The increase in zinc levels and upregulation of zinc transporters are mediated by nitric oxide in the cerebral cortex after transient ischemia in the rat [J]. Brain Res, 2008, 1200:89-98.

[5] Lee S J, Koh J Y. Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes [J]. Mol Brain, 2010, 3(1):30.

[6] Sensi S L, Paoletti P, Koh J Y, et al. The neurophysiology and pathology of brain zinc [J]. J Neurosci, 2011, 31(45):16076-16085.

[7] Sorensen J C, Mattsson B, Andreasen A, et al. Rapid disappearance of zinc positive terminals in focal brain ischemia[J]. Brain Res, 1989, 812(1-2):265-269.

[8] Kitamura Y, Iida Y, Abe J, et al. In vivo measurement of presynaptic Zn²⁺ release during forebrain ischemia in rats [J]. Biol Pharm Bull, 2006, 29(4):821-823.

[9] Lauritzen M, Dreier J P, Fabricius M, et al. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury [J]. J Cereb Blood Flow Metab, 2011, 31(1): 17-35.

[10] Carter R E, Aiba I, Dietz R M, et al. Spreading depression and related events are significant sources of neuronal Zn²⁺ release and accumulation [J]. J Cereb Blood Flow Metab, 2011, 31(4):1073-1084.

[11] Shuttleworth C W, Weiss J H. Zinc: new clues to diverse roles in brain ischemia [J]. Trends Pharmacol Sci, 2011, 32(8):480-486.

[12] Frederickson C J, Giblin L J, Krezel A, et al. Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion [J]. Exp Neurol, 2006, 198(2):285-293.

[13] Sensi S L, Ton-That D, Sullivan P G, et al. Modulation of mitochondrial function by endogenous Zn²⁺ pools [J]. Proc Natl Acad Sci U S A, 2003, 100(10):6157-6162.

[14] Lee J Y, Kim J H, Palmiter R D, et al. Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury [J]. Exp Neurol, 2003, 184(1): 337-347.

[15] Malaiyandi L M, Dineley K E, Reynolds I J. Divergent consequences arise from metallothionein overexpression in astrocytes: zinc buffering and oxidant-induced zinc release [J]. Glia, 2004, 45(4):346-353.

[16] Koumura A, Hamanaka J, Shimazawa M, et al. Metallothionein-III knockout mice aggravates the neuronal damage after transient focal cerebral ischemia [J]. Brain Res, 2009, 1292:148-154.

[17] Aras M A, Hara H, Hartnett K A, et al. Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning [J]. J Neurochem, 2009, 110(1):106-117.

[18] Gazaryan I G, Krasinskaya I P, Kristal B S, et al. Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition [J]. J Biol Chem, 2007, 282(33):24373-24380.

[19] Galasso S L, Dyck R H. The role of zinc in cerebral ischemia [J]. Mol Med, 2007, 13(7-8):380-387.

[20] Dineley K E, Richards L L, Votyakova T V, et al. Zinc causes loss of membrane potential and elevates reactive oxygen species in rat brain mitochondria [J]. Mitochondrion, 2005, 5(1): 55-65.

[21] Bonanni L, Chachar M, Jover-Mengual T, et al. Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain [J]. J Neurosci, 2006, 26(25): 6851-6862.

[22] Medvedeva Y V, Lin B, Shuttleworth C W, et al. Intracellular Zn²⁺ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia [J]. J Neurosci, 2009, 29(4):1105-1114.

[23] Aimo L, Cherr G N, Oteiza P I,et al. Low extracellular zinc increases neuronal oxidant production through NADPH oxidase and nitric oxide synthase activation [J]. Free Radic Biol Med, 2010, 48(12):1577-1587.

[24] Calderone A, Jover T, Noh K M, et al. Ischemic insults derepress the gene silencer REST in neurons destined to die [J]. J Neurosci, 2003, 23(6):2112-2121.

[25] Lapucci A, Pittelli M, Rapizzi E, et al. Poly(ADP-ribose) polymerase-1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription [J]. Mol Pharmacol, 2011, 79(6): 932-940.

[26] Kim Y H, Koh J Y. The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture[J]. Exp Neurol, 2002, 177(2), 407-418.

[27] Yu S W, Andrabi S A, Wang H, et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death[J]. Proc Natl Acad Sci U S A, 2006, 103(48):18314-18319.

[28] Andrabi S A, Kim N S, Yu S W, et al. Poly(ADP-ribose) (PAR) polymer is a death signal [J]. Proc Natl Acad Sci U S A, 2006, 103(48):18308-18313.

[29] Lee J Y, Kim Y H, Koh J Y. Protection by pyruvate against transient forebrain ischemia in rats [J]. J Neurosci, 2001, 21(20):RC171.

[30] Alano C C, Garnier P, Ying W, et al. NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death [J]. J Neurosci, 2010, 30(8):2967-2978.

[31] Sheline C T, Behrens M M, Choi D W. Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis [J]. J Neurosci, 2000, 20(9):3139-3146.

[32] Cai A L, Zipfel G J, Sheline C T. Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway [J]. Eur. J Neurosci, 2006, 24(8):2169-2176.

[33] Suh S W, Aoyama K, Alano C C, et al. Zinc inhibits astrocyte glutamate uptake by activation of poly(ADP-ribose) polymerase-1 [J]. Mol Med, 2007, 13(7-8): 344-349.

[34] Kauppinen T M, Higashi Y, Suh S W, et al. Zinc triggers microglial activation [J]. J Neurosci, 2008, 28(22):5827-5835.

[35] Irving E A, Bamford M. Role of mitogen- and stress-activated kinases in ischemic injury [J]. J Cereb Blood Flow Metab, 2002, 22(6):631-647.

[36] Redman P T, Hartnett K A, Aras M A, et al. Regulation of apoptotic potassium currents by coordinated zinc-dependent signaling [J]. J Physiol, 2009, 587(Pt 18):4393-4404.

[37] Chu C T, Levinthal D J, Kulich S M, et al. Oxidative neuronal injury. The dark side of ERK1 /2 [J]. Eur J Biochem, 2004, 271(11): 2060-2066.

[38] He K, Aizenman E. ERK signaling leads to mitochondrial dysfunction in extracellular zinc-induced neurotoxicity [J]. J Neurochem, 2010, 114(2): 452-461.

[39] 李森, 闫峰, 闫颖, 等.大鼠局灶性脑缺血损伤后半暗带区锌离子的变化 [J]. 中国神经免疫学和神经病学杂志, 2012, 19(3): 175-178.

[40] Lee S B, Bae I H, Bae Y S, et al. Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death [J]. J Biol Chem, 2006, 281(47): 36228-36235.

[41] Jia Y, Jeng J M, Sensi S L, et al. Zn²⁺ currents are mediated by calcium-permeable AMPA/kainate channels in cultured murine hippocampal neurons [J]. J Physiol, 2002, 543(Pt1): 35-48.

[42] Gower-Winter S D, Levenson C W. Zinc in the central nervous system: From molecules to behavior [J]. Biofactors, 2012, 38(3):186-193.