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Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.

ABSTRACT: Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N-myc downstream-regulated gene 2 (NDRG2), a well-studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na⁺ transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin-4 and Na⁺ -K⁺ -ATPase β1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na⁺ -K⁺ -ATPase β1 in NDRG2-knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood-brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na⁺ and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema.

SUBMITTER: Guo H

PROVIDER: S-EPMC7754347 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.

Guo Hang H Yin Anqi A Ma Yulong Y Fan Ze Z Tao Liang L Tang Wenhong W Ma Yaqun Y Hou Wugang W Cai Guohong G Zhuo Lixia L Zhang Jian J Li Yan Y Xiong Lize L

Glia 20200711 2

Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N-myc downstream-regulated gene 2 (NDRG2), a well-studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na<sup>+</sup> transfer, and astrocyte swe ...[more]

PMID: 32652708

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Project description:Background: Thrombolysis with tissue plasminogen activator (tPA) remains the only approved drug therapy for acute ischemic stroke. However, delayed tPA treatment is associated with an increased risk of brain hemorrhage. In this study, we assessed whether QiShenYiQi (QSYQ), a compound Chinese medicine, can attenuate tPA-induced brain edema and hemorrhage in an experimental stroke model. Methods: Male mice were subjected to ferric chloride-induced carotid artery thrombosis followed by mechanical detachment of thrombi. Then mice were treated with QSYQ at 2.5 h followed by administration of tPA (10 mg/kg) at 4.5 h. Hemorrhage, infarct size, neurological score, cerebral blood flow, Evans blue extravasation, FITC-labeled albumin leakage, tight and adherens junction proteins expression, basement membrane proteins expression, matrix metalloproteinases (MMPs) expression, leukocyte adhesion, and leukocyte infiltration were assessed 24 h after tPA administration. Results: Compared with tPA alone treatments, the combination therapy of QSYQ and tPA significantly reduced hemorrhage, infarction, brain edema, Evans blue extravasation, albumin leakage, leukocyte adhesion, MMP-9 expression, and leukocyte infiltration at 28.5 h after stroke. The combination also significantly improved the survival rate, cerebral blood flow, tight and adherens junction proteins (occludin, claudin-5, junctional adhesion molecule-1, zonula occludens-1, VE-cadherin, α-catenin, β-catenin) expression, and basement membrane proteins (collagen IV, laminin) expression. Addition of QSYQ protected the downregulated ATP 5D and upregulated p-Src and Caveolin-1 after tPA treatment. Conclusion: Our results show that QSYQ inhibits tPA-induced brain edema and hemorrhage by protecting the blood-brain barrier integrity, which was partly attributable to restoration of energy metabolism, protection of inflammation and Src/Caveolin signaling activation. The present study supports QSYQ as an effective adjunctive therapy to increase the safety of delayed tPA thrombolysis for ischemic stroke.

Dataset Information

Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.

Publications

Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.

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