Coadministration of FTY720 and rt-PA in an experimental model of large hemispheric stroke–no influence on functional outcome and blood–brain barrier disruption

Experimental & Translational Stroke Medicine

Waltraud Pfeilschifter¹  Christian Foerch²  Robert Brunkhorst¹  Sepide Kashefiolasl³  Ferdinand Bohmann²  Frieder Schlunk²  Aijia Cai² 

[1] Department of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany;Department of Neurology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany;Department of Neurosurgery, University Hospital, Goethe University Frankfurt, Frankfurt, Germany

关键词: Blood–brain barrier;    Hemorrhage;    Brain;    S1P1 receptor;    Sphingolipid;    Fingolimod;    FTY720;    Thrombolysis;    MCAO;    Stroke;   

Others  :  861531
DOI  :  10.1186/2040-7378-5-11

 received in 2013-09-20, accepted in 2013-10-14,  发布年份 2013

【 摘 要 】

Background

Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the standard of acute stroke care. Its potential to increase the risk of secondary intracerebral hemorrhage, especially if administered late, has been ascribed to its proteolytic activity that has detrimental effects on blood–brain barrier (BBB) integrity after stroke. FTY720 has been shown to protect endothelial barriers in several disease models such as endotoxin-induced pulmonary edema and therefore is a promising candidate to counteract the deleterious effects of rt-PA. Besides that, every putative neuroprotectant that will be eventually forwarded into clinical trials should be tested in conjunction with rt-PA.

Methods

We subjected C57Bl/6 mice to 3 h filament-induced tMCAO and postoperatively randomized them into four groups (n = 18/group) who received the following treatments directly prior to reperfusion: 1) vehicle-treatment, 2) FTY720 1 mg/kg i.p., 3) rt-PA 10 mg/kg i.v. or 4) FTY720 and rt-PA as a combination therapy. We measured functional neurological outcome, BBB disruption by quantification of EB extravasation and MMP-9 activity by gelatin zymography.

Results

We observed a noticeable increase in mortality in the rt-PA/FTY720 cotreatment group (61%) as compared to the vehicle (33%), the FTY720 (39%) and the rt-PA group (44%). Overall, functional neurological outcome did not differ significantly between groups and FTY720 had no effect on rt-PA- and stroke-induced BBB disruption and MMP-9 activation.

Conclusions

Our data show that FTY720 does not improve functional outcome and BBB integrity in large hemispheric infarctions, neither alone nor in conjunction with rt-PA. These findings stand in contrast to a recently published study that showed beneficial effects of FTY720 in combination with thrombolysis in a thrombotic model of MCAO leading to circumscript cortical infarctions. They might therefore represent a caveat that the coadministration of these two drugs might lead to excess mortality in the setting of a severe stroke.

【 授权许可】

   
2013 Cai et al.; licensee BioMed Central Ltd.

【 图 表 】

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