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MicroRNA-27b inhibition promotes Nrf2/ARE pathway activation and alleviates intracerebral hemorrhage-induced brain injury.

ABSTRACT: Oxidative stress and neuroinflammation are the key factors leading to secondary brain injury after intracerebral hemorrhage (ICH). We investigated the effects of miR-27b, an oxidative stress-responsive microRNA, on ICH-induced brain injury in rats. The ICH model was induced by intracerebral injection of collagenase. Following ICH, miR-27b expression in the striatum was reduced, whereas expression of Nrf2 mRNA and protein was increased. In PC12 cells, overexpression of miR-27b reduced expression of Nrf2, Hmox1, Sod1 and Nqo1, while miR-27b inhibition had the opposite effects. Dual luciferase reporter assays showed that Nrf2 mRNA was a direct target of miR-27b. Intracerebroventricular injection of miR-27b antagomir and transfection of miR-27b inhibitor inhibited endogenous miR-27b in rats and PC12 cells, respectively. MiR-27b antagomir promoted activation of the ICH-induced Nrf2/ARE pathway and reduced the lipid peroxidation, neuroinflammation, cell death and neurological deficits otherwise seen after ICH. In PC12 cells, the miR-27b inhibitor diminished iron-induced oxidative stress, inflammation and apoptosis, and those effects were blocked by Nrf2 knockdown. These results demonstrate that miR-27b inhibition alleviates ICH-induced brain injury, which may be explained in part by its regulation on the Nrf2/ARE pathway.

SUBMITTER: Xu W

PROVIDER: S-EPMC5642585 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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MicroRNA-27b inhibition promotes Nrf2/ARE pathway activation and alleviates intracerebral hemorrhage-induced brain injury.

Xu Wenzhe W Li Feng F Liu Zhiguo Z Xu Zhenkuan Z Sun Bin B Cao Jingwei J Liu Yuguang Y

Oncotarget 20170807 41

Oxidative stress and neuroinflammation are the key factors leading to secondary brain injury after intracerebral hemorrhage (ICH). We investigated the effects of miR-27b, an oxidative stress-responsive microRNA, on ICH-induced brain injury in rats. The ICH model was induced by intracerebral injection of collagenase. Following ICH, miR-27b expression in the striatum was reduced, whereas expression of Nrf2 mRNA and protein was increased. In PC12 cells, overexpression of miR-27b reduced expression ...[more]

PMID: 29050310

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Project description:BackgroundIntracerebral hemorrhage (ICH) induces potently oxidative stress responses and inflammatory processes. Isoliquiritigenin (ILG) is a flavonoid with a chalcone structure and can activate nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant system, negatively regulate nuclear factor-κB (NF-κB) and nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathways, but its role and potential molecular mechanisms in the pathology following ICH remain unclear. The present study aimed to explore the effects of ILG after ICH and underlying mechanisms.MethodsICH model was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male Sprague-Dawley rats weighing 280-320 g. Different doses of ILG (10, 20, or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling, respectively. Rats were intracerebroventricularly administrated with control scramble small interfering RNA (siRNA) or Nrf2 siRNA at 24 h before ICH induction, and after 24 h, ICH model was established with or without ILG (20 mg/kg) treatment. All rats were dedicated at 24 or 72 h after ICH. Neurological deficits, histological damages, brain water content (BWC), blood-brain barrier (BBB) disruption, and neuronal degeneration were evaluated; quantitative real-time RT-PCR (qRT-PCR), immunohistochemistry/immunofluorescence, western blot, and enzyme-linked immunosorbent assay (ELISA) were carried out; catalase, superoxide dismutase activities and reactive oxygen species (ROS), and glutathione/oxidized glutathione contents were measured.ResultsILG (20 and 40 mg/kg) markedly alleviated neurological deficits, histological damages, BBB disruption, brain edema, and neuronal degeneration, but there was no significant difference between two dosages. ILG (20 mg/kg) significantly suppressed the NF-κB and NLRP3 inflammasome pathways and activated Nrf2-mediated antioxidant system. Gene silencing of Nrf2 aggravated the neurological deficits, brain edema, and neuronal degeneration and increased the protein levels of NF-κB p65, NLRP3 inflammasome components, and IL-1β. ILG delivery significantly attenuated the effects of Nrf2 siRNA interference mentioned above.ConclusionsIntraperitoneal administration of ILG after ICH reduced early brain impairments and neurological deficits, and the mechanisms were involved in the regulation of ROS and/or NF-κB on the activation of NLRP3 inflammasome pathway by the triggering of Nrf2 activity and Nrf2-induced antioxidant system. In addition, our experimental results may make ILG a potential candidate for a novel therapeutical strategy for ICH.

Dataset Information

MicroRNA-27b inhibition promotes Nrf2/ARE pathway activation and alleviates intracerebral hemorrhage-induced brain injury.

Publications

MicroRNA-27b inhibition promotes Nrf2/ARE pathway activation and alleviates intracerebral hemorrhage-induced brain injury.

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