Early Loss of Blood-Brain Barrier Integrity Precedes NOX2 Elevation in the Prefrontal Cortex of an Animal Model of Psychosis

Abstract

The social isolation rearing of young adult rats is a model of psychosocial stress and provides a nonpharmacological tool to study alterations reminiscent of symptoms seen in psychosis. We have previously demonstrated that social isolation in rats leads to increased oxidative stress and to cerebral NOX2 elevations. Here, we investigated early alterations in mRNA expression leading to increased NOX2 in the brain. Rats were exposed to a short period of social isolation (1 week) and real-time polymerase chain reaction (PCR) for mRNA expression of genes involved in blood-brain barrier (BBB) formation and integrity (ORLs, Vof 21 and Vof 16, Leng8, Vnr1, and Trank 1 genes) was performed. Real-time PCR experiments, immunohistochemistry, and Western blotting analysis showed an increased expression of these genes and related proteins in isolated rats with respect to control animals. The expression of specific markers of BBB integrity, such as matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), occludin 1, and plasmalemmal vesicle associated protein-1 (PV-1), was also significantly altered after 1 week of social isolation. BBB permeability, evaluated by quantification of Evans blue dye extravasation, as well as interstitial fluid, was significantly increased in rats isolated for 1 week with respect to controls. Isolation-induced BBB disruption was also accompanied by a significant increase of Interleukin 6 (IL-6) expression. Conversely, no differences in NOX2 levels were detected at this time point. Our study demonstrates that BBB disruption precedes NOX2 elevations in the brain. These results provide new insights in the interplay of mechanisms linking psychosocial stress to early oxidative stress in the brain, disruption of the BBB, and the development of mental disorders.

Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) disruption in acute Utah electrode array implants and the effect of deferoxamine as an iron chelator on acute foreign body response

“…A BBB breach results in the infiltration of neurotoxic factors and proinflammatory myeloid cells [175, 176] and reactive oxygen and nitrogen species leading to oxidative stress in the local tissue around the electrode sites [30]. An upregulation of NADPH oxidase complexes (Figure 1) could result in the presence of various ROS that can affect BBB permeability and integrity directly by altering the expression of tight junction [177–180] and adherens junction proteins [181–183]. NOX complexes can also exacerbate IL17A-mediated ROS production and BBB disruption through increased paracellular and transcellular BBB disruption [184].…”

“…MMPs secreted from microglia and astrocytes can interact with endothelial cells by cleaving tight junctions, such as CLDN5, OCLN, and ZO1, and degrading extracellular matrix compartments [194–202], affecting paracellular integrity. The transcription of MMPs could have been influenced by the production of ROS (Figure 1), where ROS leads to an increase in the activity of MMP2 and MMP9 [180, 186–190]. An increase in MMPs occurred concurrently with decreased tight junction expression, which could have further led to BBB disruption (Figure 4).…”

Disruption of behavior and brain metabolism in artificially reared rats

“…Behavioral and neurodevelopment changes can be obtained by intermittent or even a single period of separation from the mother and siblings before or after weaning (Braun et al, 2009;Spivey et al, 2011;Kozlov et al, 2013;Barrett et al, 2015;Schiavone et al, 2017).…”

Social isolation impairs remyelination in mice through modulation of IL‐6

“…We used the cuprizone (cup) mouse model of remyelination in which myelin is depleted in the mPFC by 4 wk of cup treatment (17). Both nondemyelinated and demyelinated adult mice were assigned to social or IS experience groups in which the expressions of stressrelated cytokines, such as IL-1b and IL-6, were supposed to be different (18)(19)(20), and the effects of IS on remyelination and its underlying mechanisms were examined.…”