Estudo da influência do sexo e do efeito preventivo da N-acetilcisteína em ratos submetidos ao modelo de esquizofrenia induzido por desafio imune neonatal combinado a estresse na adolescência

Abstract

Schizophrenia is a severe and chronic mental disorder that affects over 21 million people in worldwide. The main symptoms are classed as positive (hallucinations, delusions and paranoia), negative (absence of social behaviors, anhedonia and avolition) and of cognitive nature (working memory deficit and inability to maintain attention). There is an important sex influence on the prognosis, severity of symptoms and response to the antipsychotics for this illness, with women generally displaying a better course of illness than men, probably owing the protective effects exerted by the estrogen hormone. The neurodevelopmental hypothesis that supports the pathophysiology of schizophrenia is becoming increasingly recognized. Based on it, an animal model of schizophrenia induced by "two hits" (challenges) was developed, where the first "hit" consisted of an immune activation in the neonatal phase and the second "hit" of stressors events in the peripubertal stage. N-acetylcysteine (NAC), a drug precursor of the antioxidant glutathione (GSH) has been previously used as an adjuvant in the conventional treatment of schizophrenia. Thus, our study assessed whether treatment with NAC, with dosages of 110 and 220 mg/kg, at puberty (Postnatal Day (PND) 30 to 59) was able to ameliorate behavioral and neurochemical schizophrenia-like symptoms in both male and female Wistar rats, who were also subject to neonatal immune activation (PND 5-7) induced by the viral particle poly (I:C) and underwent stressors events during puberty (PND 40-48), in order to demonstrate potential sex-specific differences. We analyzed aspects of positive-like symptoms (pre-pulse inhibition (PPI) and locomotor activity tests), negative-like (social interaction and anxiety tests) and cognition (Y Maze test). Furthermore, we investigated oxidative stress (levels of GSH, nitrite and lipid peroxidation), expression of cellular signaling proteins (AKT-phosphorylated/total, GPR30, NR2B- phosphorylated/total, parvalbumin and α7-nAChR) and the size of the hippocampus. The results showed that our two-hit model induced schizophrenia-like symptoms in both sexes, with males presenting worse "negative symptoms", while females displaying worse "positive symptoms" and an significant increase in oxidative stress in the striatum, a brain area associated with these type of symptoms. NAC improved positive, negative, cognitive symptoms, and promoted an decreased in lipid peroxidation and nitrite levels for both sexes. However, it did not prevent the anxiety-like behavior, nor rescued the GSH deficit seen in both males and females subject to the double hits. Additionally, NAC reduced the GSH levels and increased the lipid peroxidation of both male and female controls. In relation to the sex influence, the females subject to the two-hit approach responded better to the NAC treatment, as evidenced by the PPI test, the hippocampal gene expression of GPR30, parvalbumin and α7-NAChR, as well as by the size of the hippocampus. There were no significant differences in the level of Akt and NR2B activity. Our findings showed an interaction between neonatal immune activation and stressor events in adolescence leading to the development of behavioral and neurochemistry changes characteristic of adulthood schizophrenia, which can at least in part be prevented by NAC administration. This in turn reinforces the need of carefully selecting individuals and groups who would most benefit from the preventive treatment with NAC. We therefore suggest that the use of this antioxidant may be an interesting avenue for conducting further in vivo research towards its translational application for clinical neuropsychiatry practice.