Abstract
ObjectiveDelayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood‐brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti‐inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA‐induced HT after stroke.Methods and resultsWe used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA‐induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA‐treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA‐treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA‐alone‐treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down‐regulated in microglia of the RSG‐treated mice. We further found that the expression of Arg‐1 was also upregulated in those tPA and RSG‐treated stroke mice and the protection against tPA‐induced HT and BBB disruption in these mice were abolished in the presence of PPAR‐γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection).ConclusionsRSG treatment protects against BBB damage and ameliorates HT in delayed tPA‐treated stroke mice by activating PPAR‐γ and favoring microglial polarization toward anti‐inflammatory phenotype.
Highlights
By quan‐ tifying the extravasation of plasma‐derived IgG, we found that RSG treatment significantly reduced the blood‐brain barrier (BBB) disruption in stroke mice with type plasminogen activator (tPA) thrombolysis (Figure 3A,C‐D)
The present study investigated the effect of RSG treatment 1 hour prior to postischemic reperfusion on hemorrhagic transformation (HT) and BBB disruption in stroke mice with tPA thrombolysis
We found that RSG reduced acute brain infarc‐ tion and attenuated HT and BBB disruption in tPA‐treated mice 1 day after stroke
Summary
Tissue‐type plasminogen activator (tPA) is the only FDA‐approved drug therapy for acute ischemic stroke.[1,2,3] the admin‐ istration of tPA may increase the risk of hemorrhagic transforma‐ tion(HT), especially when delayed beyond 4.5 hours after the onset of ischemia,[4,5,6] leading to poor clinical outcomes in stroke patients.[7,8,9] Accumulating evidence suggests that HT is associated with disrup‐ tion of blood‐brain barrier (BBB), which may occur early after stroke and largely limit the clinical use of tPA thrombolysis for stroke pa‐ tients.[7,10,11] there is an unmet need for developing an adjuvant agent that could protect the BBB integrity and extend the therapeu‐ tic window of tPA to benefit more stroke patients for safe thrombol‐ ysis and better functional recovery.[12]. Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), a ligand‐ activated transcription factor belonging to the nuclear receptor superfamily, has been shown to orchestrate the microglia/mac‐ rophage phenotype switch from pro‐inflammatory to anti‐inflam‐ matory phenotype, leading to inhibition of inflammation and tissue repair.[13,14,15,16] Rosiglitazone(RSG), a widely used antidiabetic drug with potent PPAR‐γ activating capacity, can protect against cerebral ischemia through its anti‐inflammatory and anti‐oxidant effect.[17,18,19] it remains unknown whether RSG can be used as an adju‐ vant agent to protect the BBB integrity, especially during tPA throm‐ bolysis after stroke. We sought to assess the effects of RSG on the protection of BBB integrity in tPA‐treated stroke mice and explore the underlying mechanism of RSG‐afforded protection against tPA‐induced HT after stroke
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