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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

Sepsis-induced oxidative damage was attenuated by apocynin treatment. a, b The MDA level was significantly increased in the PFC (24 h) and hippocampus (24 h and day 3) in the CLP + vehicle group compared with the sham groups. Apocynin treatment significantly decreased the MDA level in the PFC (24 h) and hippocampus (day 3) in the CLP + apocynin group compared with the CLP + vehicle group. There was no significant difference at other time points among the four groups. c, d No significant difference was observed in the SOD activity in the PFC and hippocampus among the four groups. Data are presented as mean ± SEM (n = 6). #p < 0.05 vs the sham groups; *p < 0.05 vs the CLP + vehicle group
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Fig4: Sepsis-induced oxidative damage was attenuated by apocynin treatment. a, b The MDA level was significantly increased in the PFC (24 h) and hippocampus (24 h and day 3) in the CLP + vehicle group compared with the sham groups. Apocynin treatment significantly decreased the MDA level in the PFC (24 h) and hippocampus (day 3) in the CLP + apocynin group compared with the CLP + vehicle group. There was no significant difference at other time points among the four groups. c, d No significant difference was observed in the SOD activity in the PFC and hippocampus among the four groups. Data are presented as mean ± SEM (n = 6). #p < 0.05 vs the sham groups; *p < 0.05 vs the CLP + vehicle group

Mentions: To assess oxidative damage in the brain of the septic mice, we measured MDA and 4-HNE levels, two markers of lipid peroxidation. We observed that MDA level was significantly increased in the PFC (24 h) and hippocampus (24 h and day 3) in the CLP + vehicle group, whereas apocynin treatment attenuated MDA level after sepsis development [one-way ANOVA; PFC (24 h): F (3, 20) = 12.437, p = 0.025; hippocampus (24 h): F (3, 20) = 10.953, p = 0.03; hippocampus (day 3): F (3, 20) = 11.982, p = 0.002; Fig. 4a, b]. In addition, we observed a progressive increase in 4-HNE level in the hippocampus within the first 3 days in the CLP + vehicle group when compared with the sham group (p < 0.05; Fig. 5a, b). Furthermore, the increased 8-OH-dG expression in the PV interneurons was prevented by apocynin treatment at day 14 after CLP [PV: one-way ANOVA; CA1: F (3, 20) = 6.838, p = 0.002; CA3: F (3, 20) = 6.009, p = 0.004]; [8-OH-dG: one-way ANOVA; CA1: F (3, 20) = 6.778, p = 0.002; CA3: F (3, 20) = 11.898, p < 0.01; Fig. 6]. However, no difference in anti-inflammatory IL-10 (p > 0.05; Fig. 3g, h) or antioxidant enzyme SOD was observed among the four groups over time (p > 0.05; Fig. 4c, d). Linear regression analysis showed that PV levels were negatively correlated with the levels of 4-HNE (r = −0.5585, p = 0.0032; Fig. 7a).Fig. 4


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)

Sepsis-induced oxidative damage was attenuated by apocynin treatment. a, b The MDA level was significantly increased in the PFC (24 h) and hippocampus (24 h and day 3) in the CLP + vehicle group compared with the sham groups. Apocynin treatment significantly decreased the MDA level in the PFC (24 h) and hippocampus (day 3) in the CLP + apocynin group compared with the CLP + vehicle group. There was no significant difference at other time points among the four groups. c, d No significant difference was observed in the SOD activity in the PFC and hippocampus among the four groups. Data are presented as mean ± SEM (n = 6). #p < 0.05 vs the sham groups; *p < 0.05 vs the CLP + vehicle group
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Fig4: Sepsis-induced oxidative damage was attenuated by apocynin treatment. a, b The MDA level was significantly increased in the PFC (24 h) and hippocampus (24 h and day 3) in the CLP + vehicle group compared with the sham groups. Apocynin treatment significantly decreased the MDA level in the PFC (24 h) and hippocampus (day 3) in the CLP + apocynin group compared with the CLP + vehicle group. There was no significant difference at other time points among the four groups. c, d No significant difference was observed in the SOD activity in the PFC and hippocampus among the four groups. Data are presented as mean ± SEM (n = 6). #p < 0.05 vs the sham groups; *p < 0.05 vs the CLP + vehicle group
Mentions: To assess oxidative damage in the brain of the septic mice, we measured MDA and 4-HNE levels, two markers of lipid peroxidation. We observed that MDA level was significantly increased in the PFC (24 h) and hippocampus (24 h and day 3) in the CLP + vehicle group, whereas apocynin treatment attenuated MDA level after sepsis development [one-way ANOVA; PFC (24 h): F (3, 20) = 12.437, p = 0.025; hippocampus (24 h): F (3, 20) = 10.953, p = 0.03; hippocampus (day 3): F (3, 20) = 11.982, p = 0.002; Fig. 4a, b]. In addition, we observed a progressive increase in 4-HNE level in the hippocampus within the first 3 days in the CLP + vehicle group when compared with the sham group (p < 0.05; Fig. 5a, b). Furthermore, the increased 8-OH-dG expression in the PV interneurons was prevented by apocynin treatment at day 14 after CLP [PV: one-way ANOVA; CA1: F (3, 20) = 6.838, p = 0.002; CA3: F (3, 20) = 6.009, p = 0.004]; [8-OH-dG: one-way ANOVA; CA1: F (3, 20) = 6.778, p = 0.002; CA3: F (3, 20) = 11.898, p < 0.01; Fig. 6]. However, no difference in anti-inflammatory IL-10 (p > 0.05; Fig. 3g, h) or antioxidant enzyme SOD was observed among the four groups over time (p > 0.05; Fig. 4c, d). Linear regression analysis showed that PV levels were negatively correlated with the levels of 4-HNE (r = −0.5585, p = 0.0032; Fig. 7a).Fig. 4

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