Sex dimorphism in isoproterenol-induced cardiac damage associated neuroinflammation and behavior in old rats

Abstract

Acute cardiac damage can be induced by isoproterenol injections in animals. The associated inflammatory response could be reflected in the brain as neuroinflammation, with potential consequences for brain function and behavior. Although cardiac responses are reported age and sex-related, for neuroinflammation and brain function this is virtually unknown. Therefore, cardiac damage and its consequences for neuroinflammation, brain function and behavior were compared in aged male and female rats. Wistar rats of 24 months of age were treated with isoproterenol (ISO, twice s.c.) or saline. Four weeks after injections, exploratory behavior and short-term memory were tested. Then, rats were sacrificed. Hearts were collected to measure cardiac damage. Brain tissue was collected to obtain measures of neuroinflammation and brain function. In male-, but not in female rats, ISO induced significant cardiac damage. Accordingly, mortality was higher in males than in females. Baseline hippocampal microglia activity was lower in females, while ISO induced neuroinflammation in both sexes, Hippocampal brain-derived neurotrophic factor expression appeared lower in females, without effects of ISO. In the open field test, ISO-treated males, but not females, displayed anxiety-like behavior. No effects of ISO were observed on short-term memory in either sex. In conclusion, sex dimorphism in effects of ISO was observed for cardiac damage and open field behavior. However, these effects could not be related to differences in hippocampal neuroinflammation or neuronal function.

Whole-body vibration as a passive alternative to exercise after myocardial damage in middle-aged female rats: Effects on the heart, the brain, and behavior

“…However, these effects were only studied in young male rats, leaving potentially different effects in female rats unrevealed. Sex dimorphism in the response to ISO was already recognized in the 70s (Wexler et al, 1974 ; Wexler and Greenberg, 1979 ), and supported by our group (Toth et al, 2022b ).…”

“…Accordingly, in the present study, the ISO-induced increases in BDNF in the sedentary rats were completely reversed by exercise as well as by WBV. Since most of the results of exercise-induced increases in BDNF expression were obtained in male subjects, the deviant results in female rats in the present study may well be attributed to sex dimorphism (Toth et al, 2022b ).…”

“…Acute cardiac damage was induced by isoproterenol hydrochloride (ISO; C 11 H 7 NO 3 ·HCl: ISO), a non-selective β-adrenoceptor agonist that mimics the histological, physical, and endocrinological events of human myocardial infarction presumably by myocardial hyperactivity-induced ischemia and energy depletion (Wexler et al, 1968 ). Rats were injected subcutaneously with ISO (Sigma Aldrich) in a dose of 70 mg/kg dissolved in 1 ml/kg saline (Toth et al, 2021 , 2022a , b ). Control animals received 1 ml/kg saline.…”

“…Labeling was visualized by using a 0.075 mg/mL diaminobenzidine (DAB) solution activated with 0.1% H 2 O 2 . Sections were mounted onto glass slides and photographs were taken from the dorsal hippocampus (hippocampus) at 200 times magnification (Toth et al, 2022b ). Microglia morphology was analyzed in the different areas of the dorsal hippocampus: CA1, CA3, dentate gyrus (DG), and hilus, according to our previous publication (Hovens et al, 2014a ), regarding coverage, density, cell size, cell body area, and processes area.…”

“…In brief, sections were blocked for 1 h with 5% normal goat serum, then incubated with 1:1,000 rabbit-anti BDNF antibody (Alomone Labs, Israel) in 1% BSA, followed by incubation with 1:5,000 goat-antirabbit secondary antibody (Jackson, Wet Grove, USA). Photographs were taken at 50× magnification (Toth et al, 2022b ) from the different areas of the dorsal hippocampus, CA1, CA3, DG, and hilus, and BDNF expression was obtained as corrected optical density (Image-J) compared to an underlying reference area (Hovens et al, 2014b ).…”