期刊
CNS NEUROSCIENCE & THERAPEUTICS
卷 25, 期 12, 页码 1343-1352出版社
WILEY
DOI: 10.1111/cns.13260
关键词
blood-brain barrier; cerebral ischemia; hemorrhagic transformation; microglia; Rosiglitazone; stroke; tPA
资金
- National Natural Science Foundation of China [81971096, 81722017, 20181805, 81971223, 81771236]
- Shanghai Municipal Education Commission
- Puong New Area Health and Family Planning Commission [PWZxq2017-06]
- Shanghai Municipal Natural Science Foundation [16ZR1420700, 19411971200, 81901985]
- Shanghai Science and Technology Committee
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-gamma (PPAR-gamma), 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-gamma 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-gamma and favoring microglial polarization toward anti-inflammatory phenotype.
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