title: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Schiavone
authors.affiliation: Department of Physiology and Pharmacology, "Sapienza", University of Rome, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mhillaj
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Neri
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Morgese
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tucci
authors.affiliation: Department of Physiology and Pharmacology, "Sapienza", University of Rome, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Bove
authors.affiliation: Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
authors.forename: Mario
authors.initials: M
authors.lastname: Valentino
authors.affiliation: Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Giovanni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Pomara
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Turillazzi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy. luigia.trabace@unifg.it.
authors.forename: Luigia
authors.initials: L
authors.lastname: Trabace
authors.affiliation: Department of Physiology and Pharmacology, "Sapienza", University of Rome, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cuomo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D000074662:NADPH Oxidase 2 / Q000096:biosynthesis*; D017397:Prefrontal Cortex / Q000201:enzymology* / Q000473:pathology; D011618:Psychotic Disorders / Q000201:enzymology* / Q000473:pathology / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D012934:Social Isolation / Q000523:psychology*
chemical_list: C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2
keywords: Blood-brain barrier; NADPH oxidase; Oxidative stress; Psychosis; Social isolation