Abstract
We recently showed that inhibition of hypoxia-induced factor-1α (HIF-1α) decreased acute ischemic stroke-induced blood-brain barrier (BBB) damage. However, factors that induce the upregulation of HIF-1α expression remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase played a critical role in reperfusion-induced BBB damage after stroke. However, the role of NADPH oxidase in BBB injury during the acute ischemia stage remains unclear. This study is aimed at investigating the role of NADPH oxidase in BBB injury and the expression of HIF-1α after acute ischemic stroke. A sutured middle cerebral artery occlusion (MCAO) model was used to mimic ischemic stroke in rats. Our results show that the inhibition of NADPH oxidase by apocynin can significantly reduce the BBB damage caused by 2 h ischemic stroke accompanied by reducing the degradation of tight junction protein occludin. In addition, treatment with apocynin significantly decreased the upregulation of HIF-1α induced by 2 h MCAO. More importantly, apocynin could also inhibit the MMP-2 upregulation. Of note, HIF-1α was not colocalized with a bigger blood vessel. Taken together, our results showed that inhibition of NADPH oxidase-mediated HIF-1α upregulation reduced BBB damage accompanied by downregulating MMP-2 expression and occludin degradation after 2 h ischemia stroke. These results explored the mechanism of BBB damage after acute ischemic stroke and may help reduce the associated cerebral hemorrhage transformation after thrombolysis and endovascular treatment after ischemic stroke.
Highlights
The blood-brain barrier (BBB) which is composed of microvascular endothelial cells, astrocytes, neurons, pericytes, and basement membrane could prevent blood components from entering the brain parenchyma and maintain the basic stability of the brain environment
This study demonstrated that (1) pretreatment with Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin significantly reduced the injury of BBB integrity and disruption of occludin induced by 2 hours of ischemia, (2) pretreatment with apocynin reduced increase of hypoxia-induced factor-1α (HIF-1α) expression induced by 2 hours of ischemia, (3) apocynin could inhibit the matrix metalloproteinase-2 (MMP-2) upregulation after 2 h ischemic stroke, and (4) HIF-1α is not colocalized with bigger blood vessels
The results demonstrate that in the case of acute cerebral ischemia, inhibiting NADPH oxidase can reduce the increase of HIF-1α and upregulation of MMP-2, thereby reducing the BBB injury
Summary
The blood-brain barrier (BBB) which is composed of microvascular endothelial cells, astrocytes, neurons, pericytes, and basement membrane could prevent blood components from entering the brain parenchyma and maintain the basic stability of the brain environment. Chronic stress could induce anxiety, depression, and schizophrenia, and stress could damage the BBB integrity [1]. Previous studies have shown that BBB plays important roles in mental illnesses such as schizophrenia, autism, and depression [2] and in neurological diseases such as stroke and dementia [3]. After acute ischemic stroke, protecting the BBB is a promising strategy [4, 5] to decrease cerebral hemorrhage, the most feared complication in patients with intravenous tissue plasminogen activator (tPA) thrombolysis [6] or postendovascular treatment [7]. The mechanism of BBB disruption during the acute phase of ischemia, especially within the time window of thrombolysis [11], requires a lot of research
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