Evaluation of the role of ouabain in the hypothalamic-pituitary-adrenal axis in rats submitted to unpredictable chronic stress.

Author(s)

Jacqueline Alves Leite

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2018-12-05

Examining board members

Cristoforo Scavone; Rosana Camarini; Fernanda Marques da Cunha; Raquel Vecchio Fornari; Leticia Veras Costa Lotufo

• Advisor: Cristoforo Scavone

Abstract

Ouabain (OUA), an inhibitor of Na+, K+ -ATPase, has been identified as an endogenous substance present in human plasma, and appears to be involved in the response to acute stress in animals and humans. Chronic stress is an important aggravating factor of psychiatric illness, including depression and anxiety. In addition, cognitive problems are increasingly recognized as important components of anxiety and depression. The present work aimed to investigate the effects of OUA (1.8 <font face = \"symbol\">mg/kg) on HPA axis hyperactivity, neuroinflammation, expression of receptors and proteins involved in synaptic plasticity, behavioral effects (such as long-term memory deficit duration, depression and anxiety) and Na+,K+-ATPase activity induced by the unpredictable chronic stress protocol (CUS) performed over 14 days in rats. Our results demonstrated that intermittent treatment with OUA was able of reversing CUS-induced HPA axis hyperactivity, by reducing glucocorticoid levels, CRH-CRHR1 expression, as well as reducing CUS-induced low-grade neuroinflammation, and increase BDNF levels and expression of CRHR2 receptors. These biochemical changes contributed to a reversal in CUS-induced long-term memory impairment. In addition, animals treated only with OUA, as well as those submitted to CUS, and also treated with OUA obtained an improvement in emotional memory, which was explored in the fear conditioning test. These results suggest that the CUS protocol of 14 days promotes a neural adaptation facilitating a reassignment of the memory to the fear, here configured by the shock, and the treatment with the OUA shortens that process. In conclusion, our results suggest that intermittent treatment with OUA induces an adaptation on the HPA axis, through alterations in the expression of receptors for CRH in the hippocampus and hypothalamus, resulting in an adjustment in fear-related emotional memory. (AU)

• FAPESP's process: 14/10171-0 - Study of the molecular effect of OUA treatment on the HPA axis of rats exposed to chronic unpredictable stress
• Grantee: Jacqueline Alves Leite
• Support Opportunities: Scholarships in Brazil - Doctorate