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

Abstract

BackgroundSepsis-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.MethodsMale 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 gp91phox, 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.ResultsSepsis resulted in cognitive impairments, which was accompanied by selective phenotype loss of PV interneurons and increased gp91phox, 4-hydroxynonenal, malondialdehyde, IL-1β, and IL-6 expressions. Notably, these abnormalities could be rescued by apocynin treatment.ConclusionSelective 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.

Hippocampal β2‑microglobulin mediates sepsis‑induced cognitive impairment

“…Compared to the widely used lipopolysaccharide model, the CLP model is clinically relevant because it has a feature shared with human sepsis-induced cognitive impairment (4,13,14). Although many mechanisms, including oxidative stress, endothelial dysfunction, inflammation, unbalanced neurotransmission, mitochondrial dysfunction, and cell death have been implicated in the pathogenesis of sepsis-associated cognitive impairment (16)(17)(18)(19)(20), the precise mechanism remains to be elucidated. In this study, we showed that β2-microglobulin deficiency protected mice from sepsis-induced neurobehavioral and biochemical abnormities, suggesting β2-microglobulin may serve as a therapeutical target for sepsis-associated cognitive impairment.…”

Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder

“…This has been recently summarized as the 'interneuron energy hypothesis' [15]. Although the causes of PV interneuron loss in PTSD are not yet understood, PV interneurons are thought to be vulnerable to oxidative stress [32]. Accumulating evidence has suggested that various subunits of NADPH oxidase in the plasma membrane are highly expressed in cortical neurons and can also generate ROS [33].…”

In Vivo Imaging of Septic Encephalopathy

“…For example, there are widely discussed cytokines such as interleukins (interleukin-1, -6, -10) [37,64], tumor necrosis factor (TNF)-alpha [65,66], complement C5a [67], and cascade [68].…”