Sirt3 Mediates the Inhibitory Effect of Adjudin on Astrocyte Activation and Glial Scar Formation following Ischemic Stroke.

Xiao Yang,Yanshuang Zhang,Jiaxiang Shao,Jinfan Zhang,Keyi Geng,Weiliang Xia

doi:10.3389/fphar.2017.00943

Abstract

In response to stroke-induced injury, astrocytes can be activated and form a scar. Inflammation is an essential component for glial scar formation. Previous study has shown that adjudin, a potential Sirt3 activator, could attenuate lipopolysaccharide (LPS)- and stroke-induced neuroinflammation. To investigate the potential inhibitory effect and mechanism of adjudin on astrocyte activation, we used a transient middle cerebral artery occlusion (tMCAO) model with or without adjudin treatment in wild type (WT) and Sirt3 knockout (KO) mice and performed a wound healing experiment in vitro. Both our in vivo and in vitro results showed that adjudin reduced astrocyte activation by upregulating Sirt3 expression. In addition, adjudin treatment after stroke promoted functional and neurovascular recovery accompanied with the decreased area of glial scar in WT mice, which was blunted by Sirt3 deficiency. Furthermore, adjudin could increase Foxo3a and inhibit Notch1 signaling pathway via Sirt3. Both the suppression of Foxo3a and overexpression of N1ICD could alleviate the inhibitory effect of adjudin in vitro indicating that Sirt3-Foxo3a and Sirt3-Notch1 signaling pathways were involved in the inhibitory effect of adjudin in wound healing experiment.

Highlights

As a main cell population in the brain, astrocytes participate in lots of key signaling events including anti-oxidant activity, energy transfer, neurotransmitter up-take and recycling, ion homeostasis, trophic factor synthesis and neurovascular coupling (Abeysinghe et al, 2016)
We detected the mRNA level of glial fibrillary acidic protein (GFAP) in infarct region, and found that GFAP expression increased significantly at different time beginning at 2 days after transient middle cerebral artery occlusion (tMCAO) (Figure 1D)
The results showed that adjudin could significantly reduce the number of GFAP+ cell both at 4 and 7 days after stroke, indicating that astrocyte activation could be attenuated by adjudin (Figure 1H)

Summary

Introduction

As a main cell population in the brain, astrocytes participate in lots of key signaling events including anti-oxidant activity, energy transfer, neurotransmitter up-take and recycling, ion homeostasis, trophic factor synthesis and neurovascular coupling (Abeysinghe et al, 2016). In addition to these physiological functions, astrocytes activated by brain injury such as stroke have been reported to show astrogliosis which is characterized as hypertrophic morphology and over-proliferation of astrocytes (Maragakis and Rothstein, 2006). It is necessary to regulate the activation of astrocyte and reduce glial scar formation to overcome the physical barrier and promote neuronal regeneration in response to brain injury.

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Discussion

Conclusion