Objective Previously, we have shown that Danshen-Honghua (DSHH) for cognitive deficits after ischemia induced impairments of the hippocampus. Here, we investigate the effects of DSHH on stress-induced depression in menopausal rats. Methods A rat model with menopausal depression was established with bilateral ovariectomies in female SD rats followed by chronic mild stress treatment for 21 days. 40 rats were randomly divided into the sham surgery group (sham surgery and no stress treatment), surgery group (surgery with no stress treatment), surgery/stress group (surgery and stress treatment), fluoxetine group (2.4 mg·kg−1, with surgery and stress treatment), and DSHH group (35 g·kg−1, with surgery and stress treatment). The rats in the last two groups were treated with stresses together with intragastric drug administration for three weeks after the surgery. Then open-field locomotor scores and sucrose intake were tested for behavior changes. Also, the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and cortisone were determined by high-performance liquid chromatography (HPLC). Serum estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were determined by radioimmunoassay. Results The results of open-field locomotor scores, sucrose intake in both the fluoxetine group and DSHH group, were significantly higher than those of the surgery/stress group (P < 0.01). Serum LH, FSH, and cortisone levels in both the DSHH group and fluoxetine group were significantly lower than those in the surgery/stress group (P < 0.01). Serum E2 levels in these groups were slightly increased in these medicine groups (P < 0.01). The monoamine levels in the DSHH group were much higher than those in the surgery/stress group (P < 0.01). Conclusion DSHH can ameliorate stress-induced depressed syndromes in the surgery/stressed rats via regulating LH and FSH levels as well as monoamine levels.
Diabetic cognitive impairment (DCI) is a common diabetic complication with hallmarks of loss of learning ability and disorders of memory and behavior. Glucocorticoid receptor (GR) dysfunction is a main reason for neuronal impairment in brain of diabetic patients. Here, we determined that ipriflavone (IP) a clinical anti-osteoporosis drug functioned as a non-steroidal GR antagonist and efficiently ameliorated learning and memory dysfunction in both type 1 and 2 diabetic mice. The underlying mechanism has been intensively investigated by assay against the diabetic mice with GR-specific knockdown in the brain by injection of adeno-associated virus (AAV)-ePHP-si-GR. IP suppressed tau hyperphosphorylation through GR/PI3K/AKT/GSK3β pathway, alleviated neuronal inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway, and protected against synaptic impairment through GR/CREB/BDNF pathway. To our knowledge, our work might be the first to expound the detailed mechanism underlying the amelioration of non-steroidal GR antagonist on DCI-like pathology in mice and report the potential of IP in treatment of DCI.
Diabetic cognitive impairment (DCI) is a common diabetic complication characterized by learning and memory deficits. In diabetic patients, hyperactivated hypothalamic-pituitary-adrenal (HPA) axis leads to abnormal increase of glucocorticoids (GCs), which causes the damage of hippocampal neurons and cognitive impairment. In this study we investigated the cognition-improving effects of a non-steroidal glucocorticoid receptor (GR) antagonist 5-chloro-N-[4-chloro-3-(trifluoromethyl) phenyl]thiophene-2-sulfonamide (FX5) in diabetic mice. Four weeks after T1DM or T2DM was induced, the mice were administered FX5 (20, 40 mg·kg−1·d−1, i.g.) for 8 weeks. Cognitive impairment was assessed in open field test, novel object recognition test, Y-maze test, and Morris water maze test. We showed that FX5 administration significantly ameliorated the cognitive impairments in both type 1 and 2 diabetic mice. Similar cognitive improvement was observed in diabetic mice following brain GR-specific knockdown by injecting AAV-si-GR. Moreover, AAV-si-GR injection occluded the cognition-improving effects of FX5, suggesting that FX5 functioning as a non-steroidal GR antagonist. In PA-treated primary neurons (as DCI model in vitro), we demonstrated that FX5 (2, 5, 10 μM) dose-dependently ameliorated synaptic impairment via upregulating GR/BDNF/TrkB/CREB pathway, protected against neuronal apoptosis through repressing GR/PI3K/AKT/GSK3β-mediated tauopathy and subsequent endoplasmic reticulum stress. In LPS-treated primary microglia, FX5 dose-dependently inhibited inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway. These beneficial effects were also observed in the hippocampus of diabetic mice following FX5 administration. Collectively, we have elucidated the mechanisms underlying the beneficial effects of non-steroidal GR antagonist FX5 on DCI and highlighted the potential of FX5 in the treatment of the disease.
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