Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

Abstract

Objective Delayed 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 results We 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). Conclusions RSG 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.

Rosiglitazone Protects Blood-Brain Barrier Integrity Following Ischemic Stroke by Reducing MMP-9 Expression Through a Caveolin-1-Dependent Pathway

“…PPAR-γ agonists, including RSG also seem to reduce recurrent stroke and total related vascular events [24]. RSG treatment can minimize ischemic stroke through a variety of mechanisms, such as inhibiting in ammation, apoptosis and oxidative stress [25][26][27]. Studies have shown that RSG can increase the expression of caveolin-1 in cancer cells and macrophages [28,29].…”

The Protective Role of Immunomodulators on Tissue-Type Plasminogen Activator-Induced Hemorrhagic Transformation in Experimental Stroke: A Systematic Review and Meta-Analysis

“…(MMPs) (Mao et al, 2017). The integrity of BBB was further damaged after tPA treatment, which would eventually lead to lethal intracerebral hemorrhage (Li et al, 2019). Therefore, limiting inflammatory responses may help to reduce the risk of brain hemorrhage and improve the safety of tPA treatment following stroke.…”

Rosiglitazone Protects Blood-Brain Barrier Integrity Following Ischemic Stroke by Reducing MMP-9 Expression Through a Caveolin-1-Dependent Pathway.

“…RSG is a widely used antidiabetic drug which activates the PPAR-γ. RSG treatment can prevent ischemic stroke through a variety of mechanisms, such as inhibiting in ammation, apoptosis and oxidative stress [24][25][26]. Studies have shown that RSG can increase the expression of caveolin-1 in cancer cells and macrophages [27,28].…”