Suppression of NDRG2 alleviates brain injury after intracerebral hemorrhage through mitigating astrocyte-drived glutamate neurotoxicity via NF-κB/GLT1 signaling

Abstract

N-myc downstream-regulated gene 2 (NDRG2), a newly identified astrocytic stress response gene, is involved in the regulation of astrocytic morphology and function, and has been indicated to be a potential therapeutic target for some central nervous system (CNS) diseases. However, the role of NDRG2 in intracerebral hemorrhage (ICH) remains unknown. Here, we reported that NDRG2 suppression exerted neuroprotection effect against hemorrhagic brain injury in ICH mice and in oxyhemoglobin (OxyHb)-treated cells. Ndrg2 knockout (Ndrg2−/−) mice exhibited reduced hematoma volume and neuronal apoptosis in perihematoma although Ndrg2 deficiency showed little effect on the initial hematoma volume after ICH induction by collagenase injection. Moreover, contrary to the increase in NDRG2 expression after ICH, the expression of glutamate transporter 1 (GLT1) in astrocytes was dramatically decreased in WT (Ndrg2+/+) mice, while which could be more maintained in Ndrg2 knockout mice following ICH. Furthermore, in terms of the mechanism of epigenetic regulation of GLT1 by NDRG2, the results showed that NDRG2 directly interacted with NF-κB, and inhibited the nuclear import and DNA binding activity of the NF-κB p65 subunit after OxyHb treatment in primary astrocytes, decreasing GLT1 transcription and impairing glutamate uptake. Overall, our findings indicate that NDRG2 plays a key role in the pathology of ICH by regulating astrocytic GLT1 expression; thus suppressing NDRG2 may be a potential therapeutic target for ICH.