Abstract
Our previous studies reported that testosterone-deprived rats developed cognitive decline as a result of increased brain oxidative stress, microglia hyperactivity, and hippocampal dysplasticity. In addition, gut dysbiosis occurred in these rats. Previous studies demonstrated that n-acetyl cysteine (NAC) and a prebiotic (inulin) improved cognition in several pathological conditions. However, its effects on cognition in the testosterone-deprived condition have never been investigated. This study hypothesized that the administration of NAC, inulin, and a combined therapy improved cognition in castrated rats. Here we report that metabolic disturbance was not observed in the ORX rats, but gut dysbiosis was found in these rats. ORX rats developed blood-brain-barrier (BBB) breakdown, and increased brain oxidative stress as indicated by increased hippocampal production of reactive oxygen species (ROS) and an increase in brain malondialdehyde level. ORX rats also demonstrated glia hyperactivation, resulting in hippocampal apoptosis, hippocampal dysplasticity, and cognitive decline. All treatments equally ameliorated cognitive decline by improving gut dysbiosis, alleviating BBB dysfunction, decreasing hippocampal ROS production, decreasing hippocampal apoptosis, and reducing microglia and astrocyte activity. These findings suggest that NAC, inulin, and the combined therapy ameliorated the deleterious effects on the brain in castrated male rats similar to those treated with testosterone.
Highlights
Testosterone, a steroid sex hormone, plays an important role in cognitive function by modulating the number of dendritic spines, and mediating the release of neurotransmitters [1], as well as being involved in synaptic formation in the brain [2]
F/B ratio of ORX rats treated with testosterone replacement and the combined therapy, but not n-acetyl cysteine (NAC) or inulin alone, were significantly reduced, when compared to that of ORX rats treated with vehicle (Figure 1A)
That increase was significantly ameliorated by all treatments (Figure 1B). These findings suggested that testosterone-deprived rats developed gut dysbiosis
Summary
Testosterone, a steroid sex hormone, plays an important role in cognitive function by modulating the number of dendritic spines, and mediating the release of neurotransmitters [1], as well as being involved in synaptic formation in the brain [2]. Male rodents with an orchiectomy demonstrated dendritic spine loss [4], which could be restored by testosterone or Dihydrotestosterone (DHT) replacement [4, 5]. Similar to those animal studies, previous studies in men demonstrated that low testosterone levels have a positive correlation with a decline in learning and www.aging-us.com memory [6]. The imbalance of gut microbiota or called “gut dysbiosis” in these conditions were indicated by an increase in the ratio of Firmicutes to Bacteroidetes (F/B ratio) and Proteobacteria [9, 10]. The beneficial effects of prebiotics were found to improve metabolic disturbance in obese animals by altering the composition and metabolism of gut microbiota [13]
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