Efeito intergeracional do estresse na infância sobre comportamentos tipo depressivos e função dos Glicocorticóides no núcleo Accumbens: potencial terapêutico da Centella Asiatica

Abstract

Major depressive disorder (MDD) is a severe condition that causes a significant loss in people’s quality of life, being one of the most prevalent forms of mental illness. Among the most relevant factors underlying MDD is childhood stress. Additionally, the lack of social support during adolescence and early adulthood can amplify the effects of childhood trauma, contributing both to triggering and increasing the severity of MDD. Maternal deprivation (MD) and social isolation (SI) in rodents are behavioral models that more naturally mimic early-life and adult-life traumas in humans. Early-life stress is also a major culprit in hypothalamic-pituitary-adrenal (HPA) axis alterations, potentially leading to glucocorticoid resistance. It is essential to highlight that changes resulting from early-life and lifelong stress can be transmitted and cause behavioral and biological impairments in the offspring of these mothers. Therefore, this study evaluated the effect of early-life MD stress combined with SI in young adulthood on both male and female rats, focusing on the first-generation and non-stressed young adults, offspring of mothers who underwent stress protocols before the gestation period. Depressive-like behaviors and gene expression of proteins involved in HPA axis function in the nucleus accumbens (NAc) were evaluated. The study also investigated the possible therapeutic effect of extract and active compound madecassic acid from the medicinal species Centella asiatica (C. asiatica) in MDD and gene expression. MD and SI stress protocols induced depressive-like behaviors in males and females in phase I. These animals showed reduced expression of NR3C1 and FKBP5 in the NAc, suggesting that childhood stress and the lack of social support in adulthood culminate in alterations in HPA axis function. Treatments with C. asiatica, madecassic acid, and escitalopram significantly reduced depressive-like behaviors and increased the expression of these genes in phase I animals. These findings suggest a potential antidepressant action of C. asiatica and its active compound, madecassic acid. Additionally, the extract and the active compound reversed the reduction in NR3C1 and FKBP5 gene expression in the NAc of first-generation animals exposed to stress. In phase II animals, pre-gestational stress in females induced depressive-like behaviors in their offspring, which were reversed by treatments with C. asiatica (males) and C. asiatica and madecassic acid (females), reinforcing the intergenerational impact of stress. However, the changes identified in phase II animal behavior were not accompanied by NR3C1 and FKBP5 gene expression alterations in the NAc. The results suggest that C. asiatica extract and the active compound madecassic acid have antidepressant potential, modulating the effects of chronic childhood stress in animals that experienced stress and in their offspring who were not subjected to stress protocols