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

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.

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

“…FTY720 treatment in pMCAO did not affect stroke outcome, findings that might suggest that any beneficial effect is through mechanisms exclusive to R/I ( 228 , 229 ). Yet another study failed to show any benefit when fingolimod was given in combination with rt-PA, thus contradicting the results of the above referenced investigation ( 245 ).…”

FTY720 Protects Against Ischemia–Reperfusion Injury by Preventing the Redistribution of Tight Junction Proteins and Decreases Inflammation in the Subacute Phase in an Experimental Stroke Model

“…Our data suggest a new mechanism by which FTY720 protects against ischemic insults, in which FTY720 preserves the BBB tight and adherens junction on the cell lamellipodia and prevents them from redistributing to the cytoplasm. In contrast, there have been conflicting reports, suggesting that co-administration of FTY720 and recombinant tissue plasminogen activator (rt-PA) can exacerbate BBB disruption [36], or that TEER of endothelial cells exposed to IFNγ and TNFα were not changed by FTY720-P administration [37]. Reports from Hla et al also showed that FTY720 facilitates selective BBB permeability to small molecules under physiological conditions.…”

Pilot study to assess visualization and therapy of inflammatory mechanisms after vessel reopening in a mouse stroke model

“…Neurological function was evaluated directly prior to the stroke surgery and at 24 h post-MCAO before the second MRI on a 14 point scale neuroscore mNSS modified by Cai et al . 39 , testing hemiparesis, gait, coordination and sensory functions.…”