Abstract
BackgroundSystemic 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Systemic thrombolysis with recombinant tissue plasminogen activator is the standard of acute stroke care
Based on the description of HARM which was defined as the presence of gadolinium extravasation into the cerebrospinal fluid (CSF) space adjacent to the infarction on the fluid-attenuated inversion recovery (FLAIR) sequence of a follow up scan after gadolinium injection for a scan that took place a few hours earlier, it became evident that preceeding blood–brain barrier (BBB) disruption was present in 73% of patients who developed hemorrhagic transformation within the hours [3]
These observations were supported by animal studies showing that cerebral ischemia leads to an increase of matrix-metalloproteinase (MMP) activity, especially of Matrix metalloproteinase-9 (MMP-9) which follows the same time course as BBB disruption after experimental stroke and that both are aggravated by treatment with recombinant tissue plasminogen activator (rt-PA) [4] and correlate with hemorrhagic transformation (HT) [5]
Summary
Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the standard of acute stroke care. Based on the description of HARM (hyperintense acute reperfusion marker) which was defined as the presence of gadolinium extravasation into the cerebrospinal fluid (CSF) space adjacent to the infarction on the fluid-attenuated inversion recovery (FLAIR) sequence of a follow up scan after gadolinium injection for a scan that took place a few hours earlier, it became evident that preceeding BBB disruption was present in 73% of patients who developed hemorrhagic transformation within the hours [3] These observations were supported by animal studies showing that cerebral ischemia leads to an increase of matrix-metalloproteinase (MMP) activity, especially of MMP-9 which follows the same time course as BBB disruption after experimental stroke and that both are aggravated by treatment with rt-PA [4] and correlate with HT [5]. Combination therapies with drugs that protect endothelial barrier function seem to be a reasonable approach to limit the risks of rt-PA treatment
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