Envolvimento de receptores tipo 1 da angiotensina II (AT1R) em modelo animal de esquizofrenia induzido por dois desafios: estudo da influência do sexo e efeito preventivo da candesartana

Abstract

Schizophrenia is a serious and chronic mental disorder that affects more than 21 million people in the world. The main symptoms are: positive (hallucinations, delusions and paranoia), negative (social isolation, anedonia and alogia) and cognitive (deficits in working memory and attention). There is a significant influence of sex on the prognosis of this disease, severity of symptoms and response to antipsychotics, with women generally having a better course of the disease than men, probably because of the protective effect of estrogen. The neurodevelopmental hypothesis that supports the pathophysiology of schizophrenia has been highlighted. Based on this, an animal model of schizophrenia induced by "two hits" was developed, the first "challenge" being an immune activation in the neonatal phase and the second "hit" composed of stress events in peripuberty. Candesartan (CAND), an angiotensin II receptor blocker (ARB) with different neuroprotective properties, has become our target in the perspective of preventing some of the neuropathological deficits characteristic of schizophrenia. Thus, our study evaluated whether preventive treatment with CAND 0.3mg / kg p.o. at puberty (postnatal day (PND) 30 to 50) was able to prevent behavioral and neurochemical symptoms of the schizophrenia type in male and female swiss mice who underwent neonatal immune activation (PND 5-7) induced by the poly (I: C) viral particle and underwent stressful events during puberty (PND35-43), evidencing the possible sex differences found. We analyzed positive type symptoms (pre-pulse Inhibition and Locomotor Activity tests), negative (Social Interaction test) and cognitive (Y-Maze test). In addition, we analyzed the AT1 receptor protein expression and nuclear transcription factor kappa B (NF-κB), oxidative stress (nitrite and lipid peroxidation), and inflammatory cytokines (IL1-β, TNF-α and IL4). The results showed that the two-hit model induced type-schizophrenia behavior in both sexes with deficits of IPP and hyperlocomotion (positive symptoms), social impairment (negative symptoms) and deficits in working memory (cognitive symptoms. In addition, a supra expression of AT1 and NF-κB receptors was shown in male animals submitted to both challenges, and CAND was able to prevent this increase in this sex. In addition, CAND was able to prevent the increase in lipid peroxidation in the hippocampus (males) and plasma (both sexes), and the increase in nitrite levels in the hippocampus (females only) and plasma (both sexes) in the animals submitted to the two challenges model As for cytokines IL1β, IL4 and TNFα in the hippocampus, only male animals submitted to the model presented high levels, and CAND was efficient in preventing this choice Our results point to an interaction between neonatal immune challenge and stressful events in adolescence, contributing to the development of behavioral and neurochemical changes such as schizophrenia in adulthood, which can be prevented in part by treatment with CAND. In this way, we suggest that the use of BRAs may be an interesting alternative for conducting research with animal models with translational validity in psychiatry.