N-myc downstream-regulated gene 2 protects blood-brain barrier integrity following cerebral ischemia.

Abstract

Disruption of the blood-brain barrier (BBB) following cerebral ischemia is closely related to the infiltration of peripheral cells into the brain, progression of lesion formation, and clinical exacerbation. However, the mechanism that regulates BBB integrity, especially after permanent ischemia, remains unclear. Here, we present evidence that astrocytic N-myc downstream-regulated gene 2 (NDRG2), a differentiation- and stress-associated molecule, may function as a modulator of BBB permeability following ischemic stroke, using a mouse model of permanent cerebral ischemia. Immunohistological analysis showed that the expression of NDRG2 increases dominantly in astrocytes following permanent middle cerebral artery occlusion (MCAO). Genetic deletion of Ndrg2 exhibited enhanced levels of infarct volume and accumulation of immune cells into the ipsilateral brain hemisphere following ischemia. Extravasation of serum proteins including fibrinogen and immunoglobulin, after MCAO, was enhanced at the ischemic core and perivascular region of the peri-infarct area in the ipsilateral cortex of Ndrg2-deficient mice. Furthermore, the expression of matrix metalloproteinases (MMPs) after MCAO markedly increased in Ndrg2-/- mice. In culture, expression and secretion of MMP-3 was increased in Ndrg2-/- astrocytes, and this increase was reversed by adenovirus-mediated re-expression of NDRG2. These findings suggest that NDRG2, expressed in astrocytes, may play a critical role in the regulation of BBB permeability and immune cell infiltration through the modulation of MMP expression following cerebral ischemia.

• Authors: Mika Takarada-Iemata, Akifumi Yoshikawa, Hieu Minh Ta, Nahoko Okitani, Takumi Nishiuchi, Yasuhiro Aida, Tomoya Kamide, Tsuyoshi Hattori, Hiroshi Ishii, Takashi Tamatani, Thuong Manh Le, Jureepon Roboon, Yasuko Kitao, Tomohiro Matsuyama, Mitsutoshi Nakada, Osamu Hori
• Journal: Glia (Glia) Vol. 66 Issue 7 Pg. 1432-1446 (07 2018) ISSN: 1098-1136 [Electronic] United States
• PMID: 29476556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Ndr2 protein, mouse
• Proteins
• Matrix Metalloproteinase 3
• Mmp3 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Astrocytes (metabolism, pathology)
• Blood-Brain Barrier (metabolism, pathology)
• Brain Ischemia (metabolism, pathology)
• Capillary Permeability (physiology)
• Cells, Cultured
• Cerebral Cortex (metabolism, pathology)
• Disease Models, Animal
• Male
• Matrix Metalloproteinase 3 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Proteins (genetics, metabolism)
• Stroke (metabolism, pathology)