Abstract
The restoration of blood flow following thrombolytic therapy causes ischemia and reperfusion (I/R) injury leading to blood-brain barrier (BBB) disruption and subsequent brain edema in patients of ischemic stroke. Levo-tetrahydropalmatine (l-THP) occurs in Corydalis genus and some other plants. However, whether l-THP exerts protective role on BBB disrpution following cerebral I/R remains unclear. Male C57BL/6N mice (23 to 28 g) were subjected to 90 min middle cerebral artery occlusion, followed by reperfusion for 24 h. l-THP (10, 20, 40 mg/kg) was administrated by gavage 60 min before ischemia. We found I/R evoked Evans blue extravasation, albumin leakage, brain water content increase, cerebral blood flow decrease, cerebral infarction and neurological deficits, all of which were attenuated by l-THP treatment. Meanwhile, l-THP inhibited tight junction (TJ) proteins down-expression, Src kinase phosphorylation, matrix metalloproteinases-2/9 (MMP-2/9) and caveolin-1 activation. In addition, surface plasmon resonance revealed binding of l-THP to Src kinase with high affinity. Then we found Src kinase inhibitor PP2 could attenuate Evans blue dye extravasation and inhibit the caveolin-1, MMP-9 activation, occludin down-expression after I/R, respectively. In conclusion, l-THP attenuated BBB injury and brain edema, which were correlated with inhibiting the Src kinase phosphorylation.
Highlights
The caveolae-mediated transcytosis of albumin across endothelial cells[4,5]
A remarkable increase in the phosphorylation of Src kinase and MLC proteins and the expression of myosin light chain kinase (MLCK) was observed in ischemia and reperfusion (I/R) group at 24 h after reperfusion compared with Sham group, which were significantly attenuated by l-THP treatment (Fig. 5D through 5G). These results suggested that l-THP attenuated the blood-brain barrier (BBB) injury after I/R at least partly via inhibiting the expression of Matrix metalloproteinases (MMPs)-2/9 and the activation of Src/MLCK/MLC-signaling pathway
The present study demonstrated that l-THP attenuated BBB injury and brain edema induced by focal cerebral I/R, and reduced brain infarct size and neurological deficits
Summary
The caveolae-mediated transcytosis of albumin across endothelial cells[4,5]. Tight junction (TJ) between adjacent endothelial cells plays critical roles in the BBB disruption during ischemic stroke. Inhibition of the Src kinase phosphorylation is known to attenuate caveolae-mediated transcytosis of albumin[12]. Matrix metalloproteinases (MMPs), MMP-2 and MMP-9, play a critical role in BBB injury in stroke by degrading the ECM components of the BM14,15. Upregulated expression of MMP-2/9 has been shown to mediate the degradation of several TJ proteins including occludin, claudin-5, and ZO-116,17. The study was designed to investigate the role of l-THP on BBB injury after I/R, with addressing the involvement of Src kinase
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