Influência dos hormônios sexuais no modelo desenvolvimental de esquizofrenia induzido por desafio imune pós-natal

Abstract

Schizophrenia presents an important influence of sex with regard to disease onset, course, symptom severity and response to antipsychotics, with women having a later onset of the disorder when compared to men and needing lower doses of medications when of childbearing age. The main factor that differentiates the disease between men and women is believed to be sex hormones. The causes of this disorder are multifactorial and involve genetic vulnerability and environmental factors such as neurodevelopmental insults. Based on the neurodevelopmental hypothesis, an animal model of schizophrenia induced by intraperitoneal injection of the virus-like particle poly IC from 5-7 postnatal days (PN) With 21 days after birth (weaning), the animals were weaned, separated by sex, and divided into gonadectomized groups (GDX) or not (SHAM). All animals were subjected to behavioral tests of social interaction and Ymaze in PN40 and PN70, so that we could evaluate the effects of hormonal deprivation at different stages of development. After the last behavioral test, all animals were euthanized and had the hippocampus and prefrontal cortex dissected to measure oxidative (TBARS and nitrite), inflammatory (nitrite and MPO), anti-inflammatory (arginase) and expression marking parameters relative to GPER1, Iba1 and NFkB. The results showed that animals of both sexes submitted to GDX or not, were absent from evident behavioral changes in the PN40. In PN 70, male animals challenged with poly IC and submitted or not to GDX manifested deficits in working memory, while females showed no changes in this parameter. Both males and females in the poly IC + GDX group showed a deficit in social behavior. Regarding oxidative parameters, there was an increase in lipid peroxidation in the hippocampus of male animals challenged with poly IC and submitted or not to GDX. Both males and females challenged with poly IC showed increased levels of nitrite hippocampus. Only females challenged with poly IC submitted or not to GDX showed an increase in nitrite levels in the CPF. MPO increased in the CPF of poly IC females while there was a decrease in arginase. On the other hand, male animals challenged with poly IC and submitted to GDX showed increased arginase in the hippocampus. The results showed that the model induced the appearance of schizophrenia-like behaviors mainly in male animals. These changes in male animals were accompanied by an increase in oxidative and nitrosative stresses. Females, on the other hand, presented social deficit only when challenged with poly IC and submitted to GDX, which shows the protective effect of estrogen in this behavioral parameter. Furthermore, only females challenged with poly IC showed an increase in nitrite (HC and CPF), an increase in MPO (PFC) and a reduction in arginase (PFC). Females submitted to Poly I: C + GDX showed increased expression of the estrogen receptor coupled to protein G (GPER1) in the hippocampus, which did not occur in males. Furthermore, the immune challenge associated with GDX increased the expression of the Iba1 marker in the hippocampus of males and in the CPF of females, accompanied by an increase in the expression of NF-kBp65. The results therefore show an important influence of sex hormones on the changes triggered by exposure to the neonatal challenge.