Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats.

Xiang-Sheng Zhang,Tian-Wei Jiang,Qi Wu,Xin Zhang,Meng-Liang Zhou,Wei Li,Zhen-Nan Ye,Chun-Hua Hang,Ling-Yun Wu,Zong Zhuang

doi:10.1038/cddis.2016.292

Abstract

Increasing evidence indicates that sirtuin 1 (SIRT1) is implicated in a wide range of cellular functions, such as oxidative stress, inflammation and apoptosis. The aim of this study was to investigate the change of SIRT1 in the brain after subarachnoid hemorrhage (SAH) and its role on SAH-induced early brain injury (EBI). In the first set of experiments, rats were randomly divided into sham group and SAH groups at 2, 6, 12, 24, 48 and 72 h. The expression of SIRT1 was evaluated by western blot analysis, immunohistochemistry and immunofluorescence. In another set of experiments, SIRT1-specific inhibitor (sirtinol) and activator (activator 3) were exploited to study the role of SIRT1 in SAH-induced EBI. It showed that the protein level of SIRT1 was markedly elevated at the early stage of SAH and peaked at 24 h after SAH. The expression of SIRT1 could be observed in neurons and microglia, and the enhanced SIRT1 was mainly located in neurons after SAH. Administration of sirtinol inhibited the expression and activation of SIRT1 pathways after SAH, while activator 3 enhanced the expression and activation of SIRT1 pathways after SAH. In addition, inhibition of SIRT1 could exacerbate forkhead transcription factors of the O class-, nuclear factor-kappa B- and p53-induced oxidative damage, neuroinflammation and neuronal apoptosis, leading to aggravated brain injury after SAH. In contrast, activator 3 treatment could reduce forkhead transcription factors of the O class-, nuclear factor-kappa B-, and p53-induced oxidative damage, neuroinflammation and neuronal apoptosis to protect against EBI. These results suggest that SIRT1 plays an important role in neuroprotection against EBI after SAH by deacetylation and subsequent inhibition of forkhead transcription factors of the O class-, nuclear factor-kappa B-, and p53-induced oxidative, inflammatory and apoptotic pathways. SIRT1 might be a new promising molecular target for SAH.

Highlights

Subarachnoid hemorrhage (SAH) is a fatal neurological injury with high morbidity and mortality rates
sirtuin 1 (SIRT1)-positive cells that were positive for glialfibrillary acidic protein cannot be found in both sham group and SAH group. These results suggested that SIRT1 was expressed in neurons and microglia rather than astrocytes, and the enhanced SIRT1 was mainly located in neurons after SAH
We demonstrated that SIRT1 was upregulated in the brain cortex after SAH

Summary

Introduction

Subarachnoid hemorrhage (SAH) is a fatal neurological injury with high morbidity and mortality rates. We found that the expression level of SIRT1 was significantly increased after SAH, indicating a possible role of SIRT1 after SAH.[8] SIRT1 is a member of NAD+-dependent protein deacetylases involved in a wide variety of cellular functions by deacetylating its target proteins, including forkhead transcription factors of the O class (FoxOs), nuclear factor-kappa B (NF-кB) and p53.9,10 A growing body of evidence has demonstrated that FoxOs-, NF-кB and p53 play important roles in modulating oxidative, inflammatory and apoptotic processes.[3,9,11] Importantly, a considerable number of experimental studies have demonstrated that SIRT1 can protect neuronal survival against FoxOs-, NF-кB- and p53-induced oxidative, inflammatory and apoptotic pathways.[12,13,14,15] It seems that elevating SIRT1 activity is a valid target for the treatment of SAH.

Objectives

Methods

Results

Conclusion