Abstract
Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of miR-210 provided neuroprotection in neonatal HI brain injury. The present study aims to determine the role of miR-210 in the regulation of BBB integrity in the developing brain. miR-210 mimic was administered via intracerebroventricular injection (i.c.v.) into the brain of rat pups. Forty-eight hours after the injection, a modified Rice-Vannucci model was conducted to produce HI brain injury. Post-assays included cerebral edema analysis, western blotting, and immunofluorescence staining for serum immunoglobulin G (IgG) leakage. The results showed that miR-210 mimic exacerbated cerebral edema and IgG leakage into the brain parenchyma. In contrast, inhibition of miR-210 with its complementary locked nucleic acid oligonucleotides (miR-210-LNA) significantly reduced cerebral edema and IgG leakage. These findings suggest that miR-210 negatively regulates BBB integrity in the neonatal brain. Mechanistically, the seed sequences of miR-210 were identified complementary to the 3′ untranslated region (3′ UTR) of the mRNA transcripts of tight junction protein occludin and adherens junction protein β-catenin, indicating downstream targets of miR-210. This was further validated by in vivo data showing that miR-210 mimic significantly reduced the expression of these junction proteins in rat pup brains. Of importance, miR-210-LNA preserved the expression of junction proteins occludin and β-catenin from neonatal HI insult. Altogether, the present study reveals a novel mechanism of miR-210 in impairing BBB integrity that contributes to cerebral edema formation after neonatal HI insult, and provides new insights in miR-210-LNA mediated neuroprotection in neonatal HI brain injury.
Highlights
Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of acute mortality and morbidity in newborns with an incidence of one to eight cases per 1000 term births
The present study demonstrated that miR-210 was detrimental to the blood-brain barrier (BBB) permeability and cerebral edema formation after neonatal HI insult in rats, which was mediated by the negative regulation of BBB junction proteins occludin and β-catenin
We found that miR-210 exacerbated the vulnerability of the BBB in neonates to HI insult by increasing serum immunoglobulin G (IgG) extravasation into brain tissue and cerebral edema
Summary
Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of acute mortality and morbidity in newborns with an incidence of one to eight cases per 1000 term births. Cerebral edema is primarily caused by breakdown of the blood-brain barrier (BBB) junction complexes, and is one of the important causes in neonatal hypoxic-ischemic (HI) brain injury and brain tissue damage [6,7,8]. The disruption of junction proteins leads to increased paracellular permeability of the brain endothelial barrier in pathological conditions [16,23,24], indicating the regulation of junction proteins as an important therapeutic target for HI brain injury. The inhibition of miR-210 with complementary locked nucleic acid (LNA) oligonucleotides 4 h after brain HI insult increases the abundance of junction proteins in the brain, and significantly reduces BBB leakage and cerebral edema, suggesting a novel mechanism of the neuroprotective effect mediated by miR-210 inhibition on neonatal HIE
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