组织型纤溶酶原激活物(tPA)是一种普遍存在于血液、脑实质和神经血管单元中的丝氨酸蛋白酶,内皮组织释放的tPA主要功能是将纤溶酶原转化为纤溶酶,从而降解血凝块中纤维网;除了溶栓,tPA在中枢神经系统中也发挥着其他重要的生理学和病理学功能.作者对tPA的溶栓以外功能及其与中枢神经系统疾病之间的关系作一综述.

[1] PENNICA D,HOLMES W E,KOHR W J,et al.Cloning and expression of human tissue-type plasminogen activator cDNA in E.coli[J].Nature,1983,301(5897):214-221.
[2] SAPPINO A P,MADANI R,HUARTE J,et al.Extracellular proteolysis in the adult murine brain[J].J Clin Invest,1993,92(2):679-685.
[3] QIAN Z,GILBERT M E,COLICOS M A,et al.Tissue-plasminogen activator is induced as an immediate-early gene during seizure,kindling and long-term potentiation[J].Nature,1993,361(6411):453-457.
[4] FERNNDEZ-MONREAL M,LPEZ-ATALAYA J P,BEN-CHENANE K,et al.Arginine 260 of the amino-terminal domain of NR1 subunit is critical for tissue-type plasminogen activator-mediated enhancement of N-methyl-D-aspartate receptor signaling[J].J Biol Chem,2004,279(49):50850-50856.
[5] LEMARCHANT S,DOCAGNE F,EMERY E,et al.TPA in the injured central nervous system:Different scenarios starring the same actor？[J].Neuropharmacology,2012,62(2):749-756.
[6] PAWLAK R,MAGARINOS A M,MELCHOR J,et al.Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior[J].Nat Neurosci,2003,6(2):168-174.
[7] RODRIGUES S M,SCHAFE G E,LEDOUX J E.Molecular mechanisms underlying emotional learning and memory in the lateral amygdala[J].Neuron,2004,44(1):75-91.
[8] CHO K S,KWON K J,CHOI C S,et al.Valproic acid induces astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI-1 activity[J].Glia,2013,61(5):694-709.
[9] YEPES M,ROUSSEL B D,ALI C,et al.Tissue-type plasminogen activator in the ischemic brain:more than a thrombolytic[J].Trends Neurosci,2009,32(1):48-55.
[10] WANG Y F,TSIRKA S E,STRICKLAND S,et al.Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice[J].Nat Med,1998,4(2):228-231.
[11] YEPES M,LAWRENCE D A.Tissue-type plasminogen activator and neuroserpin:a well-balanced act in the nervous system？[J].Trends Cardiovasc Med,2004,14(5):173-180.
[12] NAGAI N,De MOL M,LIJNEN H R,et al.Role of plasminogen system components in focal cerebral ischemic infarction:a gene targeting and gene transfer study in mice[J].Circulation,1999,99(18):2440-2444.
[13] YEPES M,LAWRENCE D A.New functions for an old enzyme:nonhemostatic roles for tissue-type plasminogen activator in the central nervous system[J].Exp Biol Med,2004,229(11):1097-1104.
[14] LUKASIUK K,WILCZYNSKI G M,KACZMAREK L.Extracellular proteases in epilepsy[J].Epilepsy Res,2011,96(3):191-206.
[15] YEPES M,SANDKVIST M,COLEMAN T A,et al.Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent[J].J Clin Invest,2002,109(12):1571-1578.
[16] EAST E,BAKER D,PRYCE G,et al.A role for the plasminogen activator system in inflammation and neurodegeneration in the central nervous system during experimental allergic encephalomyelitis[J].Am J Pathol,2005,167(2):545-554.
[17] REIJERKERK A,KOOIJ G,Van Der POL S M,et al.The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier [J].J Neurochem,2010,113(2):447-453.
[18] SICONOLFI L B,SEEDS N W.Mice lacking tissue plasminogen activator and urokinase plasminogen activator genes show attenuated matrix metalloproteases activity after sciatic nerve crush [J].J Neurosci Res,2003,74(3):430-434.
[19] MELCHOR J P,STRICKLAND S.Tissue plasminogen activator in central nervous system physiology and pathology[J].Thromb Haemost,2005,93(4):655-660.
[20] MELCHOR J P,PAWLAK R,STRICKLAND S.The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration[J].J Neurosci,2003,23(26):8867-8871.
[21] LEDESMA M D,ABAD-RODRIGUEZ J,GALVAN C,et al.Raft disorganization leads to reduced plasmin activity in Alzheimer's disease brains [J].EMBO Rep,2003,4(12):1190-1196.
[22] FITCH M T,SILVER J.CNS injury,glial scars,and inflammation:Inhibitory extracellular matrices and regeneration failure [J].Exp Neurol,2008,209(2):294-301.
[23] MINOR K,PHILLIPS J,SEEDS N W.Tissue plasminogen activator promotes axonal outgrowth on CNS myelin after conditioned injury [J].J Neurochem,2009,109(3):706-715.
[24] LING C,ZOU T,HSIAO Y,et al.Disruption of tissue plasminogen activator gene reduces macrophage migration [J].Biochem Biophys Res Commun,2006,349(3):906-912.
[25] BAHI A,DREYER J L.Hippocampus-specific deletion of tissue plasminogen activator "tPA" in adult mice impairs depression-and anxiety-like behaviors[J].Eur Neuropsychopharmacol,2012,22(9):672-682.