Deletion of N‐myc downstream‐regulated gene 2 attenuates reactive astrogliosis and inflammatory response in a mouse model of cortical stab injury

Abstract

N-myc downstream-regulated gene 2 (Ndrg2) is a differentiation-and stress-associated molecule predominantly expressed in astrocytes in the CNS. In this study, we examined the expression and the role of Ndrg2 after cortical stab injury. We observed that Ndrg2 expression was elevated in astrocytes surrounding the wounded area as early as day 1 after injury in wild-type mice. Deletion of Ndrg2 resulted in lower induction of reactive astroglial and microglial markers in the injured cortex. Histological analysis showed reduced levels of hypertrophic changes in astrocytes, accumulation of microglia, and neuronal death in Ndrg2 À/À mice after injury.Furthermore, activation of the IL-6/signal transducer and activator of transcription 3 (STAT3) pathway, including the expression of IL-6 family cytokines and phosphorylation of STAT3, was markedly reduced in Ndrg2 À/À mice after injury.In a culture system, both of Il6 and Gfap were up-regulated in wild-type astrocytes treated with forskolin. Deletion of Ndrg2 attenuated induction of these genes, but did not alter proliferation or migration of astrocytes. Adenovirus-mediated reexpression of Ndrg2 rescued the reduction of IL-6 expression after forskolin stimulation. These findings suggest that Ndrg2 plays a key role in reactive astrogliosis after cortical stab injury through a mechanism involving the positive regulation of IL-6/ STAT3 signaling.

The loss of NDRG2 expression improves depressive behavior through increased phosphorylation of GSK3β

“…NDRG3 and NDRG4, on the other hand, are strongly expressed in neurons [10], and Ndrg4-deficient mice show impairments of spatial learning and neuroprotection because of a decrease in the level of BDNF [15]. Although Ndrg2-deficient mice have been reported to attenuate neuronal damage after brain injury [16], no structural or functional abnormalities in the brains of Ndrg2-deficient mice have been identified. Because mediators of cellular stress responses, such as hypoxia-inducible factor 1α (HIF-1α) [17,18] and reactive oxygen species (ROS) [19] up-regulate NDRG2 expression, NDRG2 may contribute to the modulation of stress-induced physiological and pathological processes within the nervous system.…”

N-myc downstream-regulated gene 2 in the nervous system: from expression pattern to function

“…However, in a cortical stabbing injury model in mice, both GFAP and NDRG2 were elevated, and NDRG2 showed a stress responsiveness that was related to the early astroglial activation, reactive astrogliosis, and the subsequent inflammatory response, at least in part, via the activation of IL-6/STAT3 inflammatory signaling [41]. Overall, these NDRG2 may regulate astroglial activation through the suppression of cell proliferation and the stabilization of cell morphology.…”

“…[ 41] findings demonstrated that NDRG2 is an early-stage stress-responsive gene and is correlated with astroglial activation and the subsequent inflammatory reaction. Whether the NDRG2-mediated cell stress response is an endogenous neural protection mechanism or is involved in pathological injury remains to be elucidated.…”

Osthole Enhances the Therapeutic Efficiency of Stem Cell Transplantation in Neuroendoscopy Caused Traumatic Brain Injury

“…The method we used to make a stab wound injury model was modified based on previous studies. [47][48][49] Mice were anesthetized by intraperitoneal injection of 4% chloral hydrate (1 mL/100 g). We use a needle diameter of 0.7 mm and the injury point was 2 mm left of themed line and 2.5 mm underneath the lambdoid suture (Fig.…”