Hydrogen sulphide and mild hypothermia activate the CREB signaling pathway and prevent ischemia-reperfusion injury

BMC Anesthesiology

Hai-bin Dai¹  Xiangjun Ji²  Si-hai Zhu¹  Yi-min Hu¹  Li-dong Zhang¹  Xiao-lei Miao¹  Ru-Meng Ma³  Man-lin Duan¹  Wei-yan Li¹ 

[1] Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China

[2] Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, Jiangsu, China

[3] Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China

关键词: Reperfusion injury;    Brain ischemia;    Cyclic AMP response element binding protein;    N-methyl-D-aspartate receptor;    Hypothermia;    Hydrogen sulphide;   

Others  :  1222268
DOI  :  10.1186/s12871-015-0097-6

 received in 2015-01-14, accepted in 2015-07-22,  发布年份 2015

【 摘 要 】

Background

Both hydrogen sulphide (H ₂ S) and mild hypothermia have been reported to prevent brain damage caused by reperfusion assault through regulating the N-methyl-D-aspartate receptor (NMDAR). However, the relationship between the two treatments and how they exert neuro-protective effects through NMDARs remain to be elucidated.

Methods

Transient cerebral ischemia was induced using the Pulsinelli four-vessel occlusion method. We used sodium hydrosulphide (NaHS) as the H ₂ S donor. We randomly divided 100 Sprague–Dawley rats into five groups of 20: Sham operation group (Sh), normothermic (36-37 °C) ischemia group (NT), mild hypothermic (32-33 °C) ischemia group (mHT), normothermic ischemia combined with NaHS treatment group (NT + NaHS), and mild hypothermic ischemia combined with NaHS treatment group (mHT + NaHS). After 6 hrs of reperfusion, rats were decapitated and hippocampus samples were immediately collected. We measured NR2A (GluN1), NR2B (GluN2) and p-CREB protein levels using western blotting. We further analyzed BDNF mRNA expression by real-time PCR. Hematoxylin and eosin (HE) staining was used to examine pyramidal cell histology at the CA1 region. All statistical analyses were carried out by ANOVA and LSD t-test as implemented by the SPSS 13.0 software.

Results

In the four test groups with ischemia-reperfusion, hippocampal H ₂ S concentration increased following treatment, and administration of NaHS further increased H ₂ S levels. Moreover, administration of both NaHS and mild hypothermia resulted in up-regulation of NR2A and NR2B protein expressions, as well as p-CREB protein and BDNF mRNA levels. At the cellular level, NaHS and mild hypothermia groups exhibited lower damage caused by ischemia-reperfusion in the CA1 region of the hippocampus. The strongest protective effect was observed in rats treated with combined NaHS and mild hypothermia, suggesting their effects were additive.

Conclusion

Our results support previous findings that hydrogen sulphide and mild hypothermia can prevent ischemia-reperfusion injury. Both treatments caused an up-regulation of NMDA receptors, as well as an elevation in p-CREB protein and BDNF mRNA levels. Thus, hydrogen sulphide and mild hypothermia may provide neuro-protective effect through activating the pro-survival CREB signaling pathway.

【 授权许可】

   
2015 Dai et al.

【 图 表 】

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