Chronic Unexpected Mild Stress Research Articles

Integrating serum metabolomics and network analysis to explore the antidepressant activity of crocin in rats with chronic unexpected mild stress-induced depression

Context Crocin exhibits anti-depressant properties. However, its underlying mechanisms and its relationship with metabolomics remain unclear. Objective This study elucidates the mechanism of action and potential targets of crocin in treating chronic unexpected mild stress (CUMS)-induced depression in rats. Materials and methods Male Sprague-Dawley (SD) rats underwent 4 weeks of CUMS to establish the depression model. The normal control (distilled water), crocin (25 mg/kg), and fluoxetine (5.4 mg/kg) groups were orally administered for 4-weeks. Behavioural tests evaluated the effects of crocin, while liquid chromatography-mass spectrometry metabolomics identified differential metabolites and their associated metabolic pathways. Subsequently, network pharmacology was utilized to predict the targets of crocin. Results Crocin significantly increased body weight (from 319.16 ± 4.84 g to 325.67 ± 2.84 g), sucrose preference (from 0.46 ± 0.09 to 0.70 ± 0.09), vertical activity (from 2.83 ± 1.94 to 8 ± 2.36), horizontal activity (from 1 ± 0.63 to 4.5 ± 3.08) and decreased immobilization time (from 13.16 ± 2.69 to 3.97 ± 3.00). Metabolomics analysis identified 7 metabolites and 5 associated metabolic pathways. From the combined analysis of network pharmacology and metabolomics, three targets (PRMT1, CYP3A4, and GLB1) are the overlapping targets and the two most important metabolic pathways are tryptophan metabolism and glycerolipid metabolism. Discussion and conclusions This study provides insights into the antidepressant therapeutic effect of crocin and its underlying mechanisms. The findings contribute to a better understanding of the metabolic mechanism involved in the anti-depressant effect of crocin, establishing a strong foundation for future research in this area.

Potential Therapeutic Effects of NAMPT-Mediated NAD Biosynthesis in Depression In Vivo.

This study aimed to investigate the potential therapeutic effects of nicotinamide phosphoribosyltransferase (NAMPT)-mediated adenine dinucleotide (NAD) biosynthesis in depression models in vivo. Namptflox/flox mice were used to evaluate the role of NAMPT in depression. NAMPT and NAD levels in the prefrontal cortex (PFC) were measured, and depression-associated behavior, cognitive function, and social interaction were evaluated. The expression levels of BDNF, pCREB, CREB, monoamine neurotransmitters, and corticosterone (CORT) were also detected in the PFC. The contents of NAMPT and NAD decreased in the PFC in Namptflox/flox mice. Namptflox/flox mice showed depression-like behaviors, cognitive function deterioration, decreased social ability, and decreased dominance. Meanwhile, there were decreased expression levels of the pCREB/CREB ratio, but not BDNF, in the PFC. Levels of DA, 5-HT, and NE were decreased, and CORT was activated in the PFC of Namptflox/flox mice. Additionally, the role of NAMPT-NAD was examined in rats treated with nicotinamide riboside (NR) after being exposed to chronic unexpected mild stress (CUMS). NR reversed the decreased NAMPT expression in the PFC and HIP, and the NAD content in the PFC, but not HIP in rats with CUMS-induced depression. NR also improved depressive- and anxiolytic-like behaviors, locomotor activity, and cognitive function. BDNF expression and the pCREB/CREB ratio were significantly increased in both the PFC and HIP after NR treatment. The activation of CORT and decreased content of DA were reversed after NR treatment in the PFC. There was no difference in the 5-HT content among groups in both the PFC and HIP. Taken together, NAD synthesis induced by NAMPT could be associated with depression-like behaviors in mice, and the elevated NAD level by NR improved depression in rats.

Mechanisms of Xiong-Pi-Fang in treating coronary heart disease associated with depression: A systematic pharmacology strategy and in vivo pharmacological validation

BackgroundCoronary heart disease (CHD) and depression are very common and often co-existing disorders. Xiong-Pi-Fang (XPF), a therapeutic classical traditional Chinese medicine (TCM) formula, has shown satisfactory efficacy in treating CHD associated with depression. However, its mechanism of action is still unknown. PurposeTo employ a systematic pharmacology approach for identifying the action mechanisms of XPF in treating CHD associated with depression. MethodsWe used a systematic pharmacology approach to identify the potential active mechanisms of XPF in treating CHD with depression. Potential active compounds in XPF and the diseases targets were screened using relevant databases to build corresponding pathways, following the experiments that were conducted to confirm whether the presumptive results of systemic pharmacology were correct. ResultsNetwork pharmacology predicted 42 key targets and 20 signaling pathways involved in XPF-mediated treatment, with IL-6/JAK2/STAT3/HIF-1α/VEGF-A pathway significantly affected. The common influences were hypothalamic–pituitary–adrenal axis (HPA axis) and glucocorticoid signaling, validated through chronic unexpected mild stress (CUMS) with isoprenaline (ISO) for inducing CHD within the depression model in rats. In addition, XPF intake reduced depressive-like behaviors and improved ECG ischemic changes. Furthermore, XPF exerted some anti-inflammatory effects by inhibiting the interleukin-6 (IL-6) induced phosphorylation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), ultimately downregulating hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) activation. The dysfunctional HPA axis feedback loop was also regulated, which enhanced the glucocorticoid receptor (GR) expression. In contrast, it improved glucocorticoid resistance by reducing the mineralocorticoid receptor expression. ConclusionsSuppressing IL-6 release and maintaining the HPA feedback loop balance could be the primary mechanism of XPF against CHD with depression. The significance of the IL-6 and HPA axis identified indicates their potential as essential targets for CHD therapy with depression.

CUMS and dexamethasone induce depression-like phenotypes in mice by differentially altering gut microbiota and triggering macroglia activation

BackgroundAlthough the link between gut microbiota and depression has been suggested, changes of gut microbiota vary largely among individuals with depression.AimsExplore the heterogeneity of microbiota–gut–brain axis and new pathogenic characteristics...

Increased efficacy of combining prebiotic and postbiotic in mouse models relevant to autism and depression

The Microbiota-Gut-Brain axis (MGBA) is a bidirectional communication pathway between gut bacteria and the central nervous system (CNS) (including the intestine) that exerts a profound influence on neural development, neuroinflammation, activation of stress response and neurotransmission, in addition to modulating complex behaviours, such as sociability and anxiety. Several MGBA modulating approaches are possible, such as probiotic administration. A reasonable pharmacological approach would also be the contemporarily administration of both prebiotics and postbiotics. To test this hypothesis, we probed the effects of α-lactalbumin (ALAC; a prebiotic in the dose range of 125–500 mg/kg) and sodium butyrate (NaB; a postbiotic in the dose range of 30–300 mg/kg) alone and in combination. We used two animal behavioural models of idiopathic autism, (BTBR mice) and anxiety/depression (chronic unexpected mild stress - CUMS mice) respectively, using several standard behavioural paradigms such as Three-chamber social interaction test, Marble burying assay, depression-, anxiety- and memory-tests. In BTBR autistic mice, we found that both ALAC and NaB improve animal sociability, and memory in the passive avoidance (PA); drug combination was more effective in almost all tests also reducing immobility time in the forced swimming test (FST), which was not affected by single drug administration. Similarly, in the CUMS mice, single drug administration was effective in improving: 1) depressive-like behaviour in the FST and sucrose preference test; 2) memory and learning in the PA, novel object recognition and Morris water maze tests. Drug combination was again more effective than single drug administration in most cases; however, in the CUMS model, neither single drug or combination was effective in the elevated plus maze test for anxiety. Our results suggest that in both models, ALAC and NaB combination is more effective in improving some pathological aspects of animal behaviour than single administration and that the prebiotic/postbiotic approach should be considered a reasonable approach for the manipulation of the MGBA to improve efficacy.

Trans-cinnamaldehyde shows anti-depression effect in the forced swimming test and possible involvement of the endocannabinoid system

Depression is a mental disease that significantly reduces the quality of patients’ life. Around 322 million people of all ages carry the heavy burden of depression on a worldwide scale, with a life-time prevalence of 20% according to the WHO. Trans-cinnamaldehyde (TCA) is an excellent COX-2 inhibitor in central nervous system which is a main constituent of GUIZHI as a member of traditional Chinese herb. Furthermore, previous studies demonstrated that TCA suppressed depression-like behavior in chronic unexpected mild stress, plus maze test and open field test. However, the molecular mechanism of TCA anti-depression effect is not clear. We examined the immobility of TCA pretreated male BALB/c mice in the forced swimming test (FST). Results show that TCA (50 mg/kg, po) revealed a significant effect on reduced immobility in the FST, compared with SAL group which indicated that TCA suppressed depression-like behavior. Moreover, TCA elevated the level of 5-HT and decreased the ratio of Glu/GABA in mice hippocampus. Compared with SAL + FST group, TCA + FST group significantly decreased COX-2, TRPV1 and CB1 protein level in mice hippocampus (p < 0.05, p < 0.05, p < 0.01). These findings suggest that TCA treatment exerted anti-depressive effect and was able to regulate neurotransmitters in the FST. This effect may have positive influence on the endocannabinoid (eCB) system.

Chronic Unexpected Mild Stress Destroys Synaptic Plasticity of Neurons through a Glutamate Transporter, GLT-1, of Astrocytes in the Ischemic Stroke Rat.

Background and Objective Chronic unexpected mild stress (CUMS) destroys synaptic plasticity of hippocampal regenerated neurons that may be involved in the occurrence of poststroke depression. Astrocytes uptake glutamate at the synapse and provide metabolic support for neighboring neurons. Currently, we aim to investigate whether CUMS inhibits synaptic formation of regenerated neurons through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. Method We exposed the ischemic stroke rats to ceftriaxone, during the CUMS intervention period to determine the effects of GLT-1 on glutamate circulation by immunofluorescence and mass spectrometry and its influences to synaptic plasticity by western blot and transmission electron microscopy. Result CUMS evidently reduced the level of astroglial GLT-1 in the hippocampus of the ischemic rats (p < 0.05), resulting in smaller amount of glutamate being transported into astrocytes surrounding synapses (p < 0.05), and then expression of synaptophysin was suppressed (p < 0.05) in hippocampal dentate gyrus. The ultrastructures of synapses in dentate gyrus were adversely influenced including decreased proportion of smile synapses, shortened thickness of postsynaptic density, reduced number of vesicles, and widened average distance of the synaptic cleft (all p < 0.05). Moreover, ceftriaxone can promote glutamate circulation and synaptic plasticity (all p < 0.05) by raising astroglial GLT-1 (p < 0.05) and then improve depressive behaviors of the CUMS-induced model rats (p < 0.05). Conclusion Our study shows that CUMS destroys synaptic plasticity of regenerated neurons in the hippocampus through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. This may indicate one potential pathogenesis of poststroke depression.

Influence of citicoline on citalopram-induced antidepressant activity in depressive-like symptoms in male mice

Depression is associated with significant functional disabilities. Application of new drugs which could enhance the effectiveness of antidepressants drug and reduce side effects of their long-term use seems necessary. Citicoline is used as an effective chemical agent for improving the symptoms of some neurodegenerative diseases. Therefore, in this survey, the application of citicoline as an adjuvant drug was evaluated in mice model of depression. A total of 180 adult NMRI male albino mice were used in this study. All groups were exposed to chronic unexpected mild stress (CUMS) followed by treatment with various doses of citalopram or/and citicoline or saline for 21 days. Sucrose preference (SP), open field (OF), and forced swimming test (FST) were applied to evaluate depression symptoms in the groups. The results indicated that only citicoline at the 5 mg/kg dose had shifted its status from being noneffective to become significantly effective in the co-administered group. The means of SP, OFT, and FST of the treatment groups were significantly different in favor of co-administered group compared with the other groups as well as the control group. Based on the results, it can be concluded that administration of citicoline, as an adjuvant drug, in combination with citalopram, enhanced the effectiveness of selective serotonin reuptake inhibitors (SSRI) drugs for depression treatment.

G-CSF improves CUMS-induced depressive behaviors through downregulating Ras/ERK/MAPK signaling pathway

Neuronal plasticity in hippocampal neurons is closely related to memory, mood and behavior as well as in the development of depression. Granulocyte colony-stimulating factor (G-CSF) can promote neuronal plasticity and enhance motor skills. However, the function of G-CSF in depression remains poorly understood. In this study, we explored the biological role and potential molecular mechanism of G-CSF on depression-like behaviors. Our results showed that G-CSF was significantly downregulated in the hippocampus of chronic unexpected mild stress (CUMS) rats. Administration of G-CSF significantly reversed CUMS-induced depression-like behaviors in the open field test (OFT), sucrose preference test (SPT) and forced swimming test (FST). Moreover, G-CSF upregulated the expression of synaptic-associated proteins including polysialylated form of neural cell adhesion molecule (PSA-NCAM), synaptophysin (SYN), and postsynaptic density protein 95 (PSD-95) in the hippocampus and G-CSF significantly increased cell viability rate of hippocampal neurons in vitro. Further studies indicated that the renin-angiotensin system (Ras)/extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) signaling pathways was involved in the regulation of G-CSF on depressive-like behaviors and neuronal plasticity in CUMS rats. Taken together, our results showed that G-CSF improves depression-like behaviors via inhibiting Ras/ERK/MAPK signaling pathways. Our study suggests that G-CSF may be a promising therapeutic strategy for the treatment of depression.

The involvement of homocysteine in stress-induced Aβ precursor protein misprocessing and related cognitive decline in rats.

Chronic stress is a risk factor in the development of cognitive decline and even Alzheimer's disease (AD), although its underlying mechanism is not fully understood. Our previous data demonstrated that the level of homocysteine (Hcy) was significantly elevated in the plasma of stressed animals, which suggests the possibility that Hcy is a link between stress and cognitive decline. To test this hypothesis, we compared the cognitive function, plasma concentrations of Hcy, and the brain beta-amyloid (Aβ) level between rats with or without chronic unexpected mild stress (CUMS). A lower performance by rats in behavioral tests indicated that a significant cognitive decline was induced by CUMS. Stress also disturbed the normal processing of Aβ precursor protein (APP) and resulted in the accumulation of Aβ in the brains of rats, which showed a positive correlation with the hyperhomocysteinemia (HHcy) that appeared in stressed rats. Hcy-targeting intervention experiments were used to verify further the involvement of Hcy in stress-induced APP misprocessing and related cognitive decline. The results showed that diet-induced HHcy could mimic the cognitive impairment and APP misprocessing in the same manner as CUMS, while Hcy reduction by means of vitamin B complex supplements and betaine could alleviate the cognitive deficits and dysregulation of Aβ metabolism in CUMS rats. Taken together, the novel evidence from our present study suggests that Hcy is likely to be involved in chronic stress-evoked APP misprocessing and related cognitive deficits. Our results also suggested the possibility of Hcy as a target for therapy and the potential value of vitamin B and betaine intake in the prevention of stress-induced cognitive decline.

Effects of moxibustion on the expression of tryptophan hydroxylase 2 mRNA and the activity of monoamine oxidase in depression model rats

Objective To investigate the effects of moxibustion on the expression of tryptophan hydroxylase 2(TPH2) mRNA in median raphe nuclei and the activity of monoamine oxidase (MAO) in serum and cortex in depression model rats and to explore its mechanism. Methods Female SD rats were randomly divided into control group(n=6), model group(n=7) and moxibustion group(n=7) .The rat depression model was induced by giving isolation-housing in combination with chronic unexpected mild stress(CUMS) for 21 days.The hemi-quantitative reverse transcription-polymerase chain reaction(RT-PCR) was employed to detect the relative expression of TPH2 mRNA, colorimetry was used to test the activity of MAO. Results The expression of TPH2 mRNA in median raphe nuclei in rats of the moxibustion group was higher than that in the model group(relative dentisty value: (0.3759±0.0272)vs(0.2573±0.0581), P<0.05). The activity of MAO in serum and cortex was reduced in rats of the moxibustion group((1.919±1.243 ) U/ml, (1292.048±90.072)U/mg protein, respectively) compared with that in the model group((4.117±2.727)U/ml, (1441.345 ±117.050)U/mg protein, respectively). Conclusion Moxibustion has the effects of improving depression, increasing the expression of TPH2 mRNA in median raphe nuclei and reducing the activity of MAO in serum and cortex might be one of its mechanisms. Key words: Depression; Moxibustion; Tryptophan hydroxylase 2; Monoamine oxidase

Cinnamic aldehyde treatment alleviates chronic unexpected stress-induced depressive-like behaviors via targeting cyclooxygenase-2 in mid-aged rats

Ethnopharmacological relevanceCOX-2 has been considered as a potent molecular target for prevention and therapy of depression. However, a recent study showed that COX-2 inhibitor does not improve depressive symptoms in persons aged 70 and over. Therefore, whether treatments targeting COX-2 have a clinical efficacy in depression, especially elderly individuals, remains unclear. Cinnamic aldehyde is a major constituent of Cinnamomum cassia, which has exhibited excellent anti-inflammatory activities as a COX-2 inhibitor. To investigate the potential antidepressant effect of cinnamic aldehyde in mid-aged rats. Materials and methodsThe depressive-like behaviors were measured after the rats exposed to chronic unexpected mild stress (CUMS). Cinnamic aldehyde was administrated by oral gavage to stressed rats (22.5, 45, 90mg/kg, respectively) for 21 days. The mRNA, protein expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E2 (PGE2) levels were measured in the frontal cortex and hippocampus of stressed animals. ResultsWe found that CUMS procedure not only decreased the sucrose preference, but also elevated the COX-2 activity, mRNA and protein levels, and increased PGE2 concentration in rat brain regions. Treatment with high doses of cinnamic aldehyde (45, 90mg/kg) reversed the behavioral abnormalities, and decreased the COX-2 protein and activity (but not COX-2 mRNA expression) and PGE2 concentration in frontal cortex and hippocampus of stressed rats. ConclusionCinnamic aldehyde exerted antidepressant-like effects in stressed mid-aged rats, and its mechanism of action appears to decrease COX-2 protein and activity. The current findings suggest that targeting COX-2 system might be benefit to the depression, especially elderly individuals and cinnamic aldehyde might be a promising medicine to treat the subjects in the depression.

Decreased expression of neuronal Per-Arnt-Sim domain protein 4 gene in the hippocampus of a post-stroke depression rat model

Neuronal Per-Arnt-Sim domain protein 4 (NPAS4) is important in regulating transcription and function in the limbic system and in brain development. Post-stroke depression (PSD) is a common complication following a stroke. Furthermore, organic damage as a result of a stroke affects the restoration of nerve function and indicates that hippocampal neural activity may be associated with PSD. A PSD rat model was established via a middle cerebral artery occlusion procedure, which was combined with isolation and chronic unexpected mild stress, and was used to investigate the expression of the NPAS4 gene in the hippocampus. The neurological deficit and behavior were evaluated and NPAS4 mRNA expression was measured by semi-quantitative reverse transcription-polymerase chain reaction; furthermore, the association with cognitive impairment was analyzed. The PSD rats displayed neuropsychopathic disorders and the NPAS4 mRNA expression levels in the hippocampus were significantly lower in the depression and PSD groups compared with the control group. Therefore, the present study identified that NPAS4 expression was decreased in the hippocampus of PSD rats.

Hippocampal expression of aryl hydrocarbon receptor nuclear translocator 2 and neuronal PAS domain protein 4 in a rat model of depression

The transcription factors aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) and neuronal PAS domain protein 4 (NPAS4) may influence emotion and cognitive function by regulating brain-derived neurotrophic factor expression in the hippocampus. We estimated hippocampal ARNT2 and NPAS4 expression in chronic unexpected mild stress (CUMS) rat model. The possible association was investigated between expression of these transcription factors and depressive behaviors. Behavioral tests were conducted before, during, and after 28 days of group housing or isolation plus CUMS. The sucrose solution consumption test was used to assess changes in interest and pleasure-seeking, and the open field test (OFT) was conducted to measure spontaneous activity and exploratory behavior. Expression levels of ARNT2 and NPAS4 were estimated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Compared to controls, rats subjected to isolation plus CUMS exhibited significantly reduced weight gain (t = 9.317, P = 0.000), sucrose consumption (t = 3.756, P = 0.003), horizontal ambulation (t = 2.362, P = 0.041), and number of rearings (vertical motion) (t = 2.268, P = 0.040). Relative hippocampal NPAS4 expression was significantly lower in depression model rats compared to controls (t = 2.995, P = 0.010) but there was no significant difference in hippocampal ARNT2 expression between groups (t = 0.091, P = 0.929). The relationship between the CUMS model of depression and NPAS4 expression requires further exploration.

Correlations between cognitive impairment and brain-derived neurotrophic factor expression in the hippocampus of post-stroke depression rats

The aim of this study was to investigate the correlation between brain-derived neurotrophic factor (BDNF) expression and cognitive impairment in post‑stroke depression (PSD) rats and to explore the mechanism(s) involved in the process of cognitive impairment. A rat model of focal cerebral ischemia was established by occluding the middle cerebral artery (MCA). Rats were subjected to isolation-housing combined with chronic unexpected mild stress (CUMS) to establish a PSD rat model. The learning and memory abilities of the PSD rat model were evaluated by passive avoidance tests. Real‑time PCR and immunohistochemical methods were used to detect changes in BDNF mRNA and protein expression in the hippocampus. Passive avoidance defects were revealed in the PSD and depression groups. Passive avoidance defects were more evident in the PSD group compared with the depression group and the difference was statistically significant (P<0.05). BDNF expression in the hippocampus was significantly lower in the PSD and depression groups compared with that in the normal control group (P<0.01). No significant difference in BDNF expression was identified between the normal control and stroke groups (P>0.05) or between the PSD and the depression groups (P>0.05). The decrease in BDNF expression in the hippocampus of PSD rats may aggravate cognitive impairment, however, the degree of cognitive impairment cannot be reflected by the expression levels of BDNF in the hippocampus.

P.1.d.010 Resveratrol prevents memory deficits caused by chronic unexpected mild stress in rats

P.1.d.010 Resveratrol prevents memory deficits caused by chronic unexpected mild stress in rats

Changes of spacial learning and memory abilities and ultrastructure of hippocampus in perimenopausal depression model rats

Objective To observe changes of spacial learning and memory and the ultrastructure of hippocampus in perimenopausal depression model rats. Methods Thirty-six female SD rats were randomly divided into four groups(9 in each). Normal group wasn't given any stress, and stressed group was given isolation-housing in combination with chronic unexpected mild stress (CUMS) for 21 days. Ovariectomized group was given ovary resecting, and model group was made by resecting the ovaries of female rats, then giving isolation-housing in combination with 21 days of CUMS. Morris water maze test were used to test rats' behaviors. Light microscope and transmission electron microscope were used to observe the tissular structure of hippocampus. Results After ovaries resecting and 21 days of CUMS,the escape periods of rats in model group during the first three days ( (44.08 ± 18.29)s; ( 38.80 ± 19.07 ) s; ( 22.74 ± 14.13 ) s) were longer than ovariectomizd group ( (43.68 ± 10. 37 ) s; ( 20.28 ±17.75)s;(21.22 ± 11.91 )s] and normal group( (34.50 ± 11.08)s;(21.42 ± 14.32) s;( 13.94 ±9.76) s). HE staining showed that hippocampal pyramidal cell layer became thinner in rat model of depression,the gap between cells increased,and the cells arrayed in disorder,or loosely,even a large number of cells were lost. Transmission electron microscope showed that in rats of model group, hippocampal neurons were less, nuclear collapsed, the whole nuclear membrane was fuzzy and there were some local fractures in the nuclear membrane. Mitochondria within the cytoplasm were swelling and their ridges disappeared. Conclusion The decline of spacial learning and memory abilities in perimenopausal depression model rats might result from pathological changes in hippocampus. Key words: Chronic unexpected mild stress; Perimenopausal depression; Hippocampus; Transmission electron microscope

Effect of Chinese medicine of replenishing the liver and kidney on the system of 5-HT in perimenopausal depression model rats

Objective To observe the effect of Chinese medicine of replenishing the liver and kidney on the concentration of 5-hydroxytryptamine(5-HT)in hippocampus and the expression of tryptophan hydroxylase 2 (TPH2)in median raphe nuclei in perimenopausal depression model rats and to explore its mechanism.Methods The animal model was established by resecting the ovaries of female rats,then giving isolation-housing in combination with 21 days of chronic unexpected mild stress(CUMS).High performance liquid chromatogram-electrochemical detection(HPLC-ECD)were employed to measure 5-HT in hippocampus,the hemi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)and fluorescence immunohistochemistry were employed to detect the relative expression of TPH2 mRNA and number of TPH2 immunoreactive neurons in median raphe nuclei.Results The concentration of 5-HT in hippocampus was increased in rats of the medicine group compared with that in the model group((2543.06±859.59)ng/g tissue,(1845.81±233.55)ng/g tissue,F=9.617,P＞0.05).RT-PCR showed that the relative expression of TPH2 mRNA in medicine group was much higher than that in model group ((1.282±0.158),(0.985±0.120),F=3.552,P＜0.05).Immunofluorescence showed that the number of TPH2 immunoreaetive neurons in raphe nuclei had statistical significance between medicine group and model group ((152.74±68.52),(74.12±38.01),F=7.939,P＜0.01).Conclusion Chinese medicine replenishing liver and kidney have effects of improving perimenopausal depression,increasing the expression of TPH2 in median raphe nuclei,which leads to enhance the synthesis of 5-HT in hippocampus might be one of its mechanisms. Key words: Pefimenopausal depression; 5-hydroxytryptamine; Tryptophan hydroxylase 2

Prevention of chronic stress-induced depression-like behavior by inducible nitric oxide inhibitor

Depression is associated with significant morbidity and functional disability, and it is thus important to reveal the mechanism of depression. A variety of studies suggest an involvement of neuronal nitric oxide synthase in the pathophysiological mechanism of none-stress-associated depression-like behavior in rodents. It is unknown, however, whether inducible nitric oxide synthase (iNOS) also makes contributions to the mechanism of depression. Here we show that intra-hippocampal injections of the iNOS inhibitor aminoguanidine during chronic unexpected mild stress (CUMS) suppressed CUMS-induced depression-like behavioral changes, including a reduction in sucrose preference, body weight, locomotor activity, rearing and grooming in open field test, and increased duration of immobility in forced swimming test. Thus, inhibition of hippocampal iNOS may prevent the development of CUMS model of depression.