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.
Highlights
IntroductionIn PC12 cells, overexpression of miR-27b reduced expression of Nrf, Hmox, Sod and Nqo, while miR-27b inhibition had the opposite effects
Given that nuclear factor erythroid 2-related factor 2 (Nrf2) is a likely target of miR-27b, in the present study we examined the actions of miR-27b in a rat model of intracerebral hemorrhage (ICH)-induced brain injury and in an in vitro iron toxicity model using PC12 cells
We investigated the protective effects of miR-27b inhibition on ICH rats and iron-exposed
Summary
In PC12 cells, overexpression of miR-27b reduced expression of Nrf, Hmox, Sod and Nqo, while miR-27b inhibition had the opposite effects. 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. These results demonstrate that miR-27b inhibition alleviates ICHinduced brain injury, which may be explained in part by its regulation on the Nrf2/. OS could subsequently induce expression of proinflammatory cytokines and activate nuclear factor-κB (NFκB), a key regulator of inflammatory responses [7, 8]. Our previous studies demonstrated that NF-κB activation correlated with cell death in the perihematomal area and with the outcome of ICH patients [10, 11]
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