1 Wang YF，Tsirka SE，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，1998，4：228-231.

2 Wahlgren N，Ahmed N，Dávalos A，et al.

Thrombolysis with alteplase for acute ischaemic stroke

in the safe implementation of thrombolysis in strokemonitoring

study (SITS-MOST)：an observational

study[J]. Lancet，2007，369：275-282.

3 The NINDS t-PA stroke Study Group. Intracerebral

hemorrhage after intravenous t-PA therapy for

ischemic stroke[J]. Stroke，1997，28：2019-2118.

4 Fujimura M，Gasche Y，Morita-Fujimura

Y，et al. Early appearance of activated matrix

metalloproteinase-9 and blood-brain barrier

disruption in mice after focal cerebral ischemia and

reperfusion[J]. Brain Res，1999，842：92-100.

5 Demir R，Ulvi H，Özel L，et al. Relationship between

plasma metalloproteinase-9 levels and volume and

severity of infarct in patients with acute ischemic

stroke[J]. Acta Neurol Belg，2012，112：351-356.

6 Castellanos M，Sobrino T，Millán M，et al. Serum

cellular fibronectin and matrix metalloproteinase-9

as screening biomarkers for the prediction of

parenchymal hematoma after thrombolytic therapy

in acute ischemic stroke：a multicenter confirmatory

study[J]. Stroke，2007，38：1855-1859.

7 Gartier S，Ouk T，Taqzirt M，et al. Impact of

the neutrophil response to granulocyte colonystimulating

factor on the risk of hemorrhage when

used in combination with tissue plasminogen activator

during the acute phase of experimental stroke[J]. J

Neuroinflammation，2014，11：96.

8 Carbone F，Vuilleumier N，Bertolotto M，et al.

Treatment with recombinant tissue plasminogen

activator (r-TPA) induces neutrophil degranulation in

vitro via defined pathways[J]. Vascul Pharmacol，2015，

64：16-27.

9 Solé S，Petegnief V，Gorina R，et al. Activation of

matrix metalloproteinase-3 and agrin cleavage in

cerebral ischemia/reperfusion[J]. J Neuropathol Exp

Neurol，2004，63：338-349.

10 Copin JC，Benqualid DJ，Da Silva RF，et al.

Recombinant tissue plasminogen activator induces

blood-brain barrier breakdown by a matrix

metalloproteinase-9-independent pathway after

transient focal cerebral ischemia in mouse[J]. Eur J

Neurosci，2011，34：1085-1092.

11 Suzuki Y，Nagai N，Yamakawa K，et al. Tissue-type

plasminogen activator (t-PA) induces stromelysin-1

(MMP-3) in endothelial cells through activation of

lipoprotein receptor-related protein[J]. Blood，2009，

114：3352-3358.

12 Cuadrado E，Rosell A，Penalba A，et al. Vascular

MMP-9/TIMP-2 and neuronal MMP-10 upregulation

in human brain after stroke：a combined

laser microdissection and protein array study[J]. J

Proteome Res，2009，8：3191-3197.

13 Benchenane K，Berezowski V，Ali C，et al. Tissuetype

plasminogen activator crosses the intact bloodbrain

barrier by low-density lipoprotein receptorrelated

protein-mediated transcytosis[J]. Circulation，

2005，111：2241-2249.

14 Su EJ，Fredriksson L，Gever M. et al. Activation of

PDGF-CC by tissue plasminogen activator impairs

blood-brain barrier integrity during ischemic stroke[J].

Nat Med，2008，14：731-737.

15 Suzuki Y，Nagai N，Yamakawa K，et al. Recombinant

tissue-type plasminogen activator transiently

enhances blood-brain barrier permeability during

cerebral ischemia through vascular endothelial growth

factor-mediated endothelial endocytosis in mice[J]. J

Cereb Blood Flow Metab，2015，35：2021-2031.

16 Nagai N，Yamamoto S，Tsuboi T，et al. Tissue-type

plasminogen activator is involved in the process of

neuronal death induced by oxygen-glucose deprivation

in culture[J]. J Cereb Blood Flow Metab，2001，21：

631-634.

17 Yip HK，Yuen CM，Chen KH，et al. Tissue

plasminogen activator deficiency preserves

neurological function and protects against murine

acute ischemic stroke[J]. Int J Cardiol，2016，205：

133-141.

18 Nicole O，Docagne F，Ali C，et al. The proteolytic

activity of tissue-plasminogen activator enhances

NMDA receptor-mediated signaling[J]. Nat Med，

2001，7：59-64.

19 Lesept F，Chevilley A，Jezequel J，et al. Tissuetype

plasminogen activator controls neuronal death

by raising surface dynamics of extrasynaptic NMDA

receptors[J]. Cell Death Dis，2016，7：e2466.

20 Junge CE，Sugawara T，Mannaioni G，et al. The

contribution of protease-activated receptor 1 to

neuronal damage caused by transient focal cerebral

ischemia[J]. Proc Natl Acad Sci USA，2003，100：

13 019-13 024.

21 Lapchak PA，Daley JT，Boitano PD. A blinded，

randomized study of L-arginine in small clot

embolized rabbits[J]. Exp Neurol，2015，266：143-146.

22 Harston WJ，Sutherland BA，Kennedy J，et al. The

contribution of L-arginine to the neurotoxicity of

recombinant tissue plasminogen activator following

cerebral ischemia：a review of rtPA neurotoxicity[J]. J

Cereb Blood Flow Metab，2010，30：1804-1816.

23 The National Institute of Neurological Disorders and

Stroke rt-PA Stroke Study Group. Tissue plasminogen

activator for acute ischemia stroke[J]. N Engl J Med，

1995，333：1581-1587.

24 Kwiatkowski TG，Libman RB，Frankel M，et al.

Effects of tissue plasminogen activator for acute

ischemic stroke at one year. National Institute of

Neurological Disorders and Stroke Recombinant

Tissue Plasminogen Activator Stroke Study Group[J].

N Engl J Med，1999，340：1781-1787.

25 Labiche LA，AI-Senani F，Wojner AW，et al. Is the

benefit of early recanalization sustained at 3 months?

A prospective cohort study[J]. Stroke，2003，34：695-

698.

26 Wilczak N，Elting JM，Chesik D，et al. Intravenous

tissue plasminogen activator in patients with stroke

increases the bioavailability of insulin-like growth

factor-1[J]. Stroke，2006，37：2368-2371.

27 Kurzepa J，Szpetnar M，Hordyjewska A，et al.

Thrombolytic treatment decreases glutamate/GABA

ratio in serum during acute ischaemic stroke：a pilot

study[J]. Neurol Res，2015，37：934-937.

28 Kim YH，Park JH，Hong SH，et al. Nonproteolytic

neuroprotection by human recombinant tissue

plasminogen activator[J]. Science，1999，284：647-

650.

29 Wu F，Echeverry R，Wu J，et al. Tissue-type

plasminogen activator protects neurons from

excitotoxin-induced cell death via activation of the

ERK1/2-CREB-ATF3 signal pathway[J]. Mol Cell

Neurosci，2013，52：9-19.

30 Grummisch JA，Jadavji NM，Smith PD. tPA promotes

cortical neuron survival via mTOR-dependent

mechanisms[J]. Mol Cell Neurosci，2016，74：25-33.

31 Lemarchand E，Maubert E，Haelewyn B，et al.

Stressed neurons protects themselves by a tissue-type

plasminogen activator-mediated EGFR-dependent

mechanism[J]. Cell Death Differ，2016，23：123-131.

32 Haile WB，Wu J，Echeverry R，et al. Tissue-type

plasminogen activator has a neuroprotective effect in

the ischemic brain mediated by neuronal TNF-α[J]. J

Cereb Blood Flow Metab，2012，32：57-69.

33 Louessard M，Lacroix A，Martineau M，et al. Tissue

plasminogen activator expression is restricted to

subsets of excitatory pyramidal glutamatergic

neurons[J]. Mol Neurobiol，2016，53：5000-5012.

34 Pang PT，Teng HK，Zaitsev E，et al. Cleavage of

proBDNF by tPA/plamin is essential for long-term

hippocampal plasticity[J]. Science，2004，306：487-

491.

35 Liu Z，Li Y，Zhang L，et al. Subacute intranasal

administration of tissue plasminogen activator

increases functional recovery and axonal remodeling

after stroke in rats[J]. Neurobiol Dis，2012，45：805-

809.

36 Lee HY，Hwang IY，Im H，et al. Non-proteolytic

neurotrophic effects of tissue plasminogen activator

on cultured mouse cerebrocortical neurons[J]. J

Neurochem，2007，101：1236-1247.

37 Correa F，Gauberti M，Parcq J，et al. Tissue

plasminogen activator prevents white matter damage

following stroke[J]. J Exp Med，2011，208：1229-1242.

38 Lin SY，Tang SC，Tsai LK，et al. Orolingual

angioedema after alteplase therapy of acute ischaemic

stroke：incidence and risk of prior angiotensinconverting

enzyme inhibitor use[J]. Eur J Neurol，

2014，21：1285-1291.

39 Lekoubou A，Philippeau F，Derex L，et al. Audit

report and systematic review of orolingual

angioedema in post-acute stroke thrombolysis[J].

Neurol Res，2014，36：687-694.

40 Zuo L，Wan T，Xu X，et al. Relationship of early

spontaneous type V blood pressure fluctuation after

thrombolysis in acute cerebral infarction patients and

the prognosis[J]. Sci Rep，2016，6：27 656.

41 Reinhard M，Wihler C，Roth M，et al. Cerebral

autoregulation dynamics in acute ischemic stroke

after rtPA thrombolysis[J]. Cerebrovasc Dis，2008，26：

147-155.

42 Grobholz K，Burggraf D，Martens KH，et al.

Recombinant tissue plasminogen activator attenuates

basal lamina antigen loss after experimental focal

cerebral ischemia[J]. Neurol Res，2005，27：212-217.