Depression and Heart Failure in Male and Female Rats: Role of Inflammation and Estrogens

Abstract

Clinical and preclinical studies revealed that heart failure induces depression. Injury of myocardial tissue initiates an inflammation cascade that extends to the CNS and might contribute to depression following myocardial infarction (MI). Sex differences were noticed in the progression of heart failure and depression in clinical studies. We hypothesized that depression-like behavior induced by HF post-MI is influenced by sex through modulation of inflammation pathway. First, we evaluated sex differences in depression-like behavior in male and female rats at 8-10 weeks post-MI, as well as circulating cytokines, the extent of inflammation in the PFC, PVN, and amygdala, and mBDNF levels in the PFC and amygdala that are affected by neuroinflammation. Then we evaluated the effect of ovariectomy (OVX) and whether estrogen replacement with 17β-estradiol (E2) prevents post-MI induced depression-like behavior through inhibiting neuroinflammation. Thirdly we evaluated the role of inflammation for cardiac dysfunction and development of depression-like behavior in OVX female rats post-MI by oral treatment with pentoxifylline (PTX). Male rats developed depression-like behavior by ten weeks post-MI but not females as assessed by sucrose preference test (SPT) and forced swim test (FST). Both developed similar cardiac dysfunction and a comparable increase in plasma and PVN cytokine levels, but cytokine levels increased and mBDNF levels decreased only in the PFC of male rats post-MI. OVX per se decreased sucrose consumption and induced passive behavior assessed by SPT and FST, respectively.The combination of MI and OVX aggravated depression-like behvaiour. E2 treatment prevented the development of mild depression-like behavior in OVX and severe symptoms in OVX female rats post-MI. E2 had no effect on cardiac dysfunction in OVX female rats at 10 weeks post-MI. Despite the similar increase in circulating cytokines in OVX ± E2 at 10 weeks post-MI, E2 decreased the proinflammatory cytokines and increased IL-10 (anti-inflammatory cytokine) in the PFC. Finally, we evaluated the role of neuroinflammation in depression-like behavior in OVX female rats post-MI through inhibiting cytokine production by administering oral PTX. PTX prevented depression-like behavior in OVX female rats post-MI and reduced cytokines levels in plasma, PVN and PFC. However, PTX did not affect the progression of cardiac dysfunction at 10 weeks post-MI. Sex determines the development of depression-like behavior in HF post-MI and neuroinflammation appears to play a critical pathway that is affected by sex and can be inhibited by hormonal replacement or anti-inflammatory agents.