Abstract
Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.
Highlights
Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, the effect of PerC on the blood-brain barrier (BBB) disruption and underlying mechanisms remains largely unknown
We found that limb remote PerC reduced functional neurological deficits, decreased brain edema and BBB breakdown after cerebral ischemia in the rat
Gap formation in the endothelial cells of the ischemic brain was reduced and tight junction (TJ) protein occludin was significantly increased after PerC, along with reduced expression levels of proMMP-9
Summary
Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke. MMP-9 knockout mice significantly reduced infarct volume, edema and BBB disruption, which were associated with reduced expression of TJ protein, zonula occludens-1 (ZO-1) [11], suggesting that ischemiainduced disruption of tight junction proteins is mediated by MMPs. A very recent study showed that increased BBB permeability is associated with activation of MEK/ERK1/2 in brain microvessels [12]. Our study suggested that PerC ameliorates brain edema and BBB disruption after ischemic stroke, and was associated with: 1) reduced phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and MMP-9 expression, and 2) increased expression of TJ protein occludin
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