Neuroimunomodulação e esquizofrenia: uma análise translacional

Abstract

This work is composed by two chapters. In the first chapter, a longitudinal analysis was performed in order to evaluate the impact of the maternal immune activation (MIA) by administration of the viral mimetic polyinosinic-polycytidylic acid (Poly I:C) under immune, behavioral and neuroanatomical parameters of the offspring in a sex-specific way, at different stages of life. In this sense, 20 C57/BL/6 pregnant dams were treated on gestational day 17 with Poly I:C 5mgKg or saline via intraperitoneal route. Serum collections from offspring’s (n=53) were performed at the age of 21, 35, 49 and 70 days, corresponding to juvenile, puberty, young adult and adult life stages, respectively. Inflammatory mediators were measured by the Cytometric Beads Array (CBA). Behavioral and neuroanatomical analyzes were performed at 21 months of age. Our results demonstrate that offspring exposed to MIA during intrauterine life present important and permanent changes in several immunologic parameters, with a prevalence of a pro-inflammatory profile in the Poly I:C group compared to controls and females present immune abnormalities later in relation to males. Both males and females of Poly I:C group had a smaller brain volume, although reduction in the volume of the lateral ventricles, olfactory bulb and hippocampus is observed only in male group. MIA induces anxiety-like behavior and memory impairment. However, no differences were observed in compulsive-like behavior and basal locomotor activity in both sexes and groups. We believe that these results may contribute to a new insight at prevention and future treatments of schizophrenia in an individualized way, especially when we consider that schizophrenia affects men and women at different times of life and in different ways. In the second chapter, an integrated summary of the best global evidence about immunological biomarkers of EZ will be presented, in a single, accessible and useful document, in order to consolidate knowledge gaps and reduce uncertainties for heath decision makers and managers in public health. A bibliographic search of Systematic Reviews (RSs) was performed in MEDLINE (via PubMed), CRD, Cochrane Library, BVS, EMBASE (Elsevier), APA PsycNet® and Scielo (Web of Science). Data from studies defined as low risk of bias and moderate or high methodological quality by ROBIS and AMSTAR-2 tools, respectively, were collected, analyzed and integrated. All phases of this work were carried out in duplicate by two independent reviewers, 24 with disagreements resolved by discussion. A total of 4.302 works were captured and evaluated. Of these, only 24 met all eligibility criteria. We can affirm through this work, with high quality of evidence, that inflammatory processes at different stages of life, as well as polymorphisms in the gene that encodes the anti-inflammatory cytokine IL-10, were found to be strongly associated with the increased risk of developing EZ. We also observed, with a high level of evidence, the existence of an inflammatory syndrome in the EZ, with potential Th2 inclination. Potential immune biomarkers in EZ vary according to clinical status, prognosis, severity and introduction of pharmacotherapy. Primary studies of high methodological quality, well delineated RSs, with data stratification according to the clinical status and longitudinal monitoring of EZ patients following internal and external validity checklist remains insufficient to obtain quality and more accurate information about biomarkers in EZ, especially for EZ starting in childhood.