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BRIEF RESEARCH REPORT article

Front. Endocrinol.
Sec. Neuroendocrine Science
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1500630
This article is part of the Research Topic Nuclear Receptors in Health and Disease View all articles

Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands

Provisionally accepted
Amanda Da Silva Chaves Amanda Da Silva Chaves 1Raíssa Duarte Ventura Raíssa Duarte Ventura 1Maria Florencia Pacini Maria Florencia Pacini 2Nathalia Santos Magalhães Nathalia Santos Magalhães 1Patricia Machado Rodrigues Silva Patricia Machado Rodrigues Silva 1Marco Aurélio Martins Marco Aurélio Martins 1Ana Rosa Pérez Ana Rosa Pérez 2Vinicius Frias Carvalho Vinicius Frias Carvalho 1*
  • 1 Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
  • 2 National University of Rosario, Rosario, Santa Fe, Argentina

The final, formatted version of the article will be published soon.

    We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on the impairment of the negative feedback of the HPA axis induced by N-acetylcysteine (NAC). Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after the starting of NAC supplementation. NAC reduced the expression of Nrf2 in the pituitary of mice. Furthermore, NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in the GRα expression and an increase of GRβ expression in the pituitary gland. Treatment with CoPPIX reduced adrenal enlargement, systemic corticosterone levels, and GRβ expression in the pituitary gland of mice supplemented with NAC, besides increasing the expression of GRα. CoPPIX treatment also restored the failure in the negative feedback of the HPA axis induced by NAC. In conclusion, these findings showed that NAC reduced the Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.

    Keywords: antioxidants1, glucocorticoid2, GR isoforms3, HPA axis4, Nrf-25

    Received: 23 Sep 2024; Accepted: 07 Jan 2025.

    Copyright: © 2025 Chaves, Ventura, Pacini, Magalhães, Silva, Martins, Pérez and Carvalho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Vinicius Frias Carvalho, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil

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