Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice

Journal of Neuroinflammation

Jian-Jun Yang¹  Jin-Chun Shen¹  Zhi-Yi Zuo²  Min Jia¹  Hui Zhang¹  Xiao-Ru Sun¹  Ling-Sha Ju¹  Hui Tang¹  Li-Li Qiu¹  Mu-Huo Ji¹ 

[1] Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, China;Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA

关键词: Oxidative stress;    NADPH oxidase;    Sepsis;    Cognition;    Parvalbumin interneurons;   

Others  :  1228653
DOI  :  10.1186/s12974-015-0401-x

 received in 2015-08-03, accepted in 2015-09-17,  发布年份 2015

【 摘 要 】

Background

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by many pathological events, including neuroinflammation and oxidative stress damage. Increasing evidence suggests that parvalbumin (PV) interneurons play a key role in the cognitive process, whereas the dysfunction of these interneurons has been implicated in a number of major psychiatric disorders. Here, we aimed to investigate whether enhanced inflammation and oxidative stress-mediated PV interneuron phenotype loss plays a role in sepsis-induced cognitive impairments.

Methods

Male C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg. The mice were euthanized at the indicated time points, and the brain tissues were harvested for determination of the PV, membrane subunit of NADPH oxidase gp91 ^phox , and markers of oxidative stress (4-hydroxynonenal and malondialdehyde) and inflammation (tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-10). A separate cohort of animals was used to evaluate the behavioral alterations by the open field and fear conditioning tests. Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.

Results

Sepsis resulted in cognitive impairments, which was accompanied by selective phenotype loss of PV interneurons and increased gp91 ^phox , 4-hydroxynonenal, malondialdehyde, IL-1β, and IL-6 expressions. Notably, these abnormalities could be rescued by apocynin treatment.

Conclusion

Selective phenotype loss of PV interneurons, as a result of NADPH oxidase 2 (Nox2) activation, might partly contribute to cognitive impairments in a mouse model of SAE.

【 授权许可】

   
2015 Ji et al.

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