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

Ji MH, Qiu LL, Tang H, Ju LS, Sun XR, Zhang H, Jia M, Zuo ZY, Shen JC, Yang JJ - J Neuroinflammation (2015)

Bottom Line: For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg.Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.Notably, these abnormalities could be rescued by apocynin treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China. jimuhuo2009@sina.com.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

a Schematic timeline of the experimental procedures. b Dose-response of apocynin on the fear conditioning test in mice. Data are presented as mean ± SEM (n = 10–12). #p < 0.05 vs the sham group; *p < 0.05 vs the CLP group. c Apocynin treatment did not affect the survival rate of the sepsis mice (n = 12–20)
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Fig1: a Schematic timeline of the experimental procedures. b Dose-response of apocynin on the fear conditioning test in mice. Data are presented as mean ± SEM (n = 10–12). #p < 0.05 vs the sham group; *p < 0.05 vs the CLP group. c Apocynin treatment did not affect the survival rate of the sepsis mice (n = 12–20)

Mentions: The mice were subjected to cecal ligation and puncture (CLP) as previously described [18]. Briefly, the mice were anesthetized with 2 % sodium pentobarbital in saline (50 mg/kg, intraperitoneally; Sigma, USA). A laparotomy was performed with a 1-cm midline incision through the linea alba. The cecum was isolated carefully and then ligated with 4.0 silk below the ileocecal junction, approximately 0.8 cm from the distal end. The cecum was then perforated twice with a sterile 22-gauge needle and was gently squeezed to extrude the fecal contents into the peritoneal cavity. The cecum was then returned to the peritoneal cavity, and the laparotomy was closed with 4.0 silk sutures. Sham-operated mice had the cecum isolated and then returned to the peritoneal cavity, without ligation or puncture of the cecum. All mice received subcutaneous normal saline resuscitation (20 ml/kg of body weight), and antibiotic therapy (ertapenem, 20 mg/kg; Merck Research Laboratory, USA) begun immediately after the surgery and once daily for a total of 3 days. The entire procedure was completed within 8 min. All animals were returned to their cages with free access to food and water. The flow chart for the study protocol was summarized in Fig. 1a.Fig. 1


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

Ji MH, Qiu LL, Tang H, Ju LS, Sun XR, Zhang H, Jia M, Zuo ZY, Shen JC, Yang JJ - J Neuroinflammation (2015)

a Schematic timeline of the experimental procedures. b Dose-response of apocynin on the fear conditioning test in mice. Data are presented as mean ± SEM (n = 10–12). #p < 0.05 vs the sham group; *p < 0.05 vs the CLP group. c Apocynin treatment did not affect the survival rate of the sepsis mice (n = 12–20)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587802&req=5

Fig1: a Schematic timeline of the experimental procedures. b Dose-response of apocynin on the fear conditioning test in mice. Data are presented as mean ± SEM (n = 10–12). #p < 0.05 vs the sham group; *p < 0.05 vs the CLP group. c Apocynin treatment did not affect the survival rate of the sepsis mice (n = 12–20)
Mentions: The mice were subjected to cecal ligation and puncture (CLP) as previously described [18]. Briefly, the mice were anesthetized with 2 % sodium pentobarbital in saline (50 mg/kg, intraperitoneally; Sigma, USA). A laparotomy was performed with a 1-cm midline incision through the linea alba. The cecum was isolated carefully and then ligated with 4.0 silk below the ileocecal junction, approximately 0.8 cm from the distal end. The cecum was then perforated twice with a sterile 22-gauge needle and was gently squeezed to extrude the fecal contents into the peritoneal cavity. The cecum was then returned to the peritoneal cavity, and the laparotomy was closed with 4.0 silk sutures. Sham-operated mice had the cecum isolated and then returned to the peritoneal cavity, without ligation or puncture of the cecum. All mice received subcutaneous normal saline resuscitation (20 ml/kg of body weight), and antibiotic therapy (ertapenem, 20 mg/kg; Merck Research Laboratory, USA) begun immediately after the surgery and once daily for a total of 3 days. The entire procedure was completed within 8 min. All animals were returned to their cages with free access to food and water. The flow chart for the study protocol was summarized in Fig. 1a.Fig. 1

Bottom Line: For the interventional study, the animals were chronically treated with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin, at 5 mg/kg.Primary hippocampal neuronal cultures were used to investigate the mechanisms underlying the dysfunction of PV interneurons.Notably, these abnormalities could be rescued by apocynin treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China. jimuhuo2009@sina.com.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus