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Preventive effect of estrogen on depression-like behavior induced by chronic restraint stress.

ABSTRACT: To investigate the roles of estrogen and kalirin-7 in chronic restraint stress (CRS)-induced depression and the pathophysiological mechanism of depression.Healthy female mice from Institute of Cancer Research (ICR) were randomly divided into 3 groups: control group, CRS group, and estrogen + CRS group. CRS was used to establish the animal model of depression. Forced swimming test and immunohistochemistry method were utilized to investigate the animal behavior and kalirin-7 expression in the hippocampus, respectively.Compared with the control group, the CRS mice displayed depression-like behaviors, including a significant reduction in body weight, a significant increase in immobility time in forced swimming test, and a dramatic decrease in kalirin-7 expression in the hippocampus. However, administration of estrogen attenuated the CRS-induced negative behaviors, and simultaneously increased kalirin-7 expression.Estrogen replacement therapy (ERT) could prevent CRS-induced depression-like behaviors in female ICR mice. Besides, kalirin-7 also plays a role in preventing CRS-induced depression-like behaviors.

SUBMITTER: Li W

PROVIDER: S-EPMC5560369 | biostudies-other | 2010 Apr

REPOSITORIES: biostudies-other

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Project description:The leaves of Vaccinium bracteatum Thunb. are a source of traditional herbal medicines found in East Asia. The present study aimed to evaluate the mechanisms underlying the antidepressant-like effects of water extract of V. bracteatum Thunb. leaves (VBLW) in a mouse model of chronic restraint stress (CRS) and to identify the possible molecular in vitro mechanisms of the neuroprotective effects. The CRS-exposed mice were orally administered VBLW (100 and 200 mg/kg) daily for 21 days consecutively. The behavioral effects of VBLW were assessed through the forced swim test (FST) and the open field test (OFT). The levels of serum corticosterone (CORT), corticotropin releasing hormone (CRH), and adrenocorticotropin hormone (ACTH), brain monoamines, such as serotonin, dopamine, and norepinephrine, and serotonin turnover by tryptophan hydroxylase 2 (TPH2), serotonin reuptake (SERT), and monoamine oxidase A (MAO-A) were evaluated, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway. CRS-exposed mice treated with VBLW (100 and 200 mg/kg) showed significantly reduced immobility time and increased swimming and climbing times in the FST, and increased locomotor activity in the OFT. Moreover, CRS mice treated with VBLW exhibited significantly decreased CORT and ACTH, but enhanced brain monoamine neurotransmitters. In addition, CRS mice treated with VBLW had dramatically decreased protein levels of MAO-A and SERT, but increased TPH2 protein levels in the hippocampus and the PFC. Similarly, VBLW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and the PFC. Furthermore, VBLW showed neuroprotective effects via increased CREB phosphorylation in CORT-induced cell injury that were mediated through the ERK/Akt/mTOR signaling pathways. These results suggested that the antidepressant-like effects of VBLW might be mediated by the regulation of the HPA axis, glucocorticoids, and serotonin turnover, such as TPH2, SERT, and MAO-A, as well as the concentration of monoamine neurotransmitters, and the activities of ERK and Akt phosphorylation, which were possibly associated with neuroprotective effects.

Project description:BackgroundClopidogrel is widely used to prevent and treat cardiovascular atherosclerosis and thrombosis. However, disturbance in the expression and activity of liver cytochrome metabolic enzymes significantly changes clopidogrel efficacy. Therefore, the effect of chronic unpredictable mild stress (CUMS)-induced depression on the expression of liver cytochrome metabolic enzymes and clopidogrel pharmacokinetics in rats were explored.MethodsNine different CUMSs were selected to establish a rat model of depression. Open field experiment and sucrose preference test were applied to explore the depressive behaviors. The concentration of serotonin in the cortex of depressed rats was determined using enzyme linked immunosorbent assay (ELISA). All rats were given 10 mg/kg clopidogrel orally after 12 weeks, and blood samples were collected at different time points. The clopidogrel concentration and CYP2C19/ CYP2C9 activity in rat liver microsomes were assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The rat liver drug enzymes expression was determined by Real-Time Quantitative Reverse Transcription PCR (RT-qPCR).ResultsOpen field experiment and sucrose preference test indicated the successful construction of the CUMS-induced depression model. The concentration of serotonin in the cortex of depressed rats decreased by 42.56% (∗∗ p < 0.01). The area under the curve of clopidogrel pharmacokinetics decreased by 33.13% (∗ p < 0.05) in the depression rats, while distribution volume and clearance increased significantly (∗∗ p < 0.01). The half-time and distribution volume did not significantly differ. The CYP2C19 and CYP2C9 activity of liver microsomes in the CUMS-induced depression group were significantly higher than that in the control group (∗∗ p < 0.01). CYP2C11 and CYP1A2 mRNA expression up-regulated approximately 1.3 - fold in the depressed rat livers compared with that in the control, whereas that of CYP2C13 was down-regulated by 27.43% (∗∗ p < 0.01). CYP3A1 and CYP2C12 expression were slightly up-regulated, and that of CES1 did not change.ConclusionsThese results indicated that CUMS-induced depression altered clopidogrel pharmacokinetics, and the change in CYP450 activity and expression in depressed rat livers might contribute to the disturbance of clopidogrel pharmacokinetics.

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Preventive effect of estrogen on depression-like behavior induced by chronic restraint stress.

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