Chronic Stress Group Research Articles

Maternal separation induces long-term changes in mineralocorticoid receptor in rats subjected to chronic stress and treated with tianeptine

Purpose: The aim of this study was to analyze whether early maternal separation would result in long-term, persistent alterations in stress response in adulthood, altering mineralocorticoid receptor immunoreactivity (MR-ir) in the dorsal hippocampal areas [CA1, CA2, CA3 and dentate gyrus (DG)], paraventricular nucleus of the hypothalamus and medial and central nucleus of the amygdala, key structures involved in stress response regulation. We also analyzed whether chronic treatment with the antidepressant tianeptine reverses these possible changes.Material and methods: Male Wistar rats were subjected to daily maternal separation for 4.5 h during 3 weeks or left undisturbed. As adults, they were exposed to chronic stress during 24 days or left undisturbed, and they were also daily treated with tianeptine (10 mg/kg i.p.) or isotonic solution.Results: In the CA2 and DG areas of the dorsal hippocampus, there was an increase in MR-ir in non-maternally separated and chronic stressed groups. Tianeptine raised MR-ir in the CA3. In the DG, control and maternally separated + chronic stress groups treated with tianeptine showed more MR-ir than their respective vehicle groups. In the paraventricular nucleus, tianeptine decreased MR-ir in non-separated groups, but not in maternally separated rats.Conclusions: Our results support findings that early-life events induce long-term changes in stress response regulation, persistent into adulthood, which are manifested during challenges in later life, and that treatment with tianeptine, which tends to attenuate the hypothalamus-pituitary-adrenal axis dysregulation, depends on the individual experience of each rat.

Phyllanthus emblica leaf extract ameliorates testicular damage in rats with chronic stress.

Stress affects the male reproductive system and can cause sub-fertility or infertility. Although Phyllanthus emblica L. (PE) extract has been shown to have high antioxidant capacity and protective properties in damaged tissue, the preventive effects of PE extract on testicular function from stress-related impairment have never been demonstrated. This study aimed to investigate the effects of PE aqueous leaf extract on testicular impairment and protein marker changes in rats suffering from chronic stress. Adult male rats were divided into four groups: a control group, a chronic stress (CS) group, and two groups with CS that received different doses of PE extract (50 or 100 mg/kg body weight (BW)). In the treatment groups, the animals were given PE extract daily before stress induction for 42 consecutive days. Stress was induced through immobilization (4 h/d) followed by forced cold swimming (15 min/d). Sperm quality and the histology of the testes and caudal epididymis were examined, as were levels of serum corticosterone, testosterone, and malondialdehyde (MDA). The expressions of testicular steroidogenic acute regulatory (StAR) and tyrosine-phosphorylated proteins were investigated using immuno-Western blot analysis, as these proteins are assumed to play important roles in spermatogenesis and androgen synthesis. The results showed that PE (50 mg/kg BW) significantly increased sperm concentration and testosterone levels, while decreasing corticosterone levels, MDA levels, sperm head abnormalities, and acrosome-reacted sperm in CS rats. In addition, PE at both doses was found to diminish testicular histopathology in the CS rats. We also found that 50 mg/kg BW of PE significantly improved StAR protein expression and altered the intensities of some tyrosine-phosphorylated proteins in testis. We conclude that PE leaf extract at 50 mg/kg BW can prevent testicular damage in rats with CS.

Induction of Epileptic Seizures in Mouse Models of Chronic Restraint Stress

Objective To investigate the sensitivity of mouse models of chronic restraint stress to conditions that induce epileptic seizures.Methods Male C57BL/6J mice were randomized into chronic restraint stress(CRS)group and normal control(NC)group. The modeling results were evaluated by sucrose preference test and forced swimming test. Kainic aicd(KA)was intraperitoneally injected to induce acute seizures. Seizure onset time,duration,and scores were recorded and compared.Results During the forced swimming test,the immobility time was(120.9±13.5)s in CRS group and only(59.1±9.8)s in NC group(t=3.700,P=0.0019). During the sucrose preference test,the water consumption proportion at 0-24 h and 0-48 h were(64.7±4.7)% and(73.3±3.0)%,respectively,in CRS group,significantly lower than those[(77.2±2.5)%(t=2.672,P=0.0167)and(83.0±2.8)%(t=2.386,P=0.0297)] in NC group. Although there was no significant difference in the total number of acute seizures[(11.5±1.1)times vs.(13.7±2.1)times;t=0.9767,P=0.3465],mice in CRS group had significantly higher severe seizure score than in control group[(66±10)scores vs.(37±5)scores;t=2.777,P=0.0157]. The seizure onset time was(138±26)s in CRS group,which was significantly shorter than that in NC group[(234±28)s;t=2.485,P=0.0274]. The seizure duration of the CRS group was(61±16)min,which was significantly longer than that of the NC group[(37±5)min;t=3.342,P=0.0053].Conclusion CRS mice are more susceptible to KA-induced acute epileptic seizures.

Oxidative stress effects in the uterus, placenta and fetus of pregnant rats submitted to acute and chronic stress.

To evaluate the effects of oxidative stress in pregnant rats submitted to acute and chronic stress, relating to alterations in the uterus, placenta and fetus. Twenty-four female Wistar albino (Rattus norvegicus), were divided into four groups, for induction of oxidative stress the animals were submitted to cold and physical immobilization. Plasma fasting glucose and MDA were determined in all groups and the fetuses and placentas were measured. There were no statistical differences in the levels of malonic dialdehyde (MDA), however the averages of chronic stress group were higher compared to control groups, which could explain the observed adverse effects; there was no correlation between puppies' size, the weight of the placenta and MDA values. Chronic stress causes adverse effects, when compared to control groups; chronic stress group had fetuses, placentas and number of puppies, significantly lower compared to other groups. The rats exposed to chronic stress, also presented a higher frequency of fetal resorption.

Chronic stress and high sucrose intake cause distinctive morphometric effects in the adrenal glands of post-weaned rats

ABSTRACT We investigated the effects of chronic stress combined with high sucrose intake on the morphology of the adrenal glands in young rats. Male Wistar rats were fed a standard chow diet and allocated into control (C; tap water), chronic restraint stress (St), 30% sucrose diet (S30) and 30% sucrose diet + chronic restraint stress (S30 + St) groups. St consisted of 1 h daily sessions, 5 days/week for 4 weeks. Chronic stress reduced the thickness of the zona glomerulosa (ZG) and zona fasciculata (ZF) in both right and left glands; the thickness of the zona reticularis (ZR) was increased in the right gland. Cell density was greater in the ZF and medulla of both right and left glands, whereas cell density increased in the ZR of only the left gland. The percentage of small cells was lower in the ZG, whereas more large cells were found in the left gland. A similar result was obtained for the ZF, ZR and medulla in both right and left glands. Chronic stress increased the area covered by blood vessels in the ZR of the right gland, but decreased the area in the ZR of the left gland. The area covered by blood vessels was reduced in the medulla of both right and left glands in rats subjected to chronic stress. Infiltration of immune cells was increased by chronic stress in all layers of the cortex of the left gland, but was reduced in the medulla of the right gland. A high sucrose diet reduced the thickness of the medulla in the left gland. Cell proliferation increased in the ZG of the right gland and the weight of the right adrenal gland increased. Reduced cell proliferation in the ZG of the left gland was associated with a reduction in the area covered by blood vessels. In addition, the area covered by blood vessels decreased in the medulla of both glands. Our findings demonstrate that exposure to chronic stress during early life causes morphometric changes in adrenal glands.

Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling

Chronic stress is a psychologically significant factor that impairs learning and memory in the hippocampus. Insulin signaling is important for the development and cognitive function of the hippocampus. However, the relation between chronic stress and insulin signaling at the molecular level is poorly understood. Here, we show that chronic stress impairs insulin signaling in vitro and in vivo, and thereby induces deficits in hippocampal spatial working memory and neurobehavior. Corticosterone treatment of mouse hippocampal neurons in vitro caused neurotoxicity with an increase in the markers of autophagy but not apoptosis. Corticosterone treatment impaired insulin signaling from early time points. As an in vivo model of stress, mice were subjected to chronic restraint stress. The chronic restraint stress group showed downregulated insulin signaling and suffered deficits in spatial working memory and nesting behavior. Intranasal insulin delivery restored insulin signaling and rescued hippocampal deficits. Our data suggest that psychological stress impairs insulin signaling and results in hippocampal deficits, and these effects can be prevented by intranasal insulin delivery.

Abstract 134: Dysbiosis of gut microbiota in chronic stressed patients with endometriosis

Abstract Although endometriosis is a benign disease, it has malignant characters such as invasion and migration. Besides, there is an endometrial type of ovarian cancer, which means endometriosis is similar to malignant disease at some extent. Existing researches showed that patients with endometriosis often have high level of chronic stress. Furthermore, chronic stress can promote the growth of endometriosis by activating the β-adrenergic signaling pathway. Gut microbiota is reported to be related to the stress level through the gut-brain axis. So we wonder whether gut microbiota is associated with chronic stress level in endometriosis patients, which may provide a new clinical intervention method to improve prognosis. We grouped the endometriosis patients into stress group and control group with GAD-7 and PHQ-9 questionnaires and collected patients' fecal and tissues samples. Gut microbiota compositions were analyzed by the 16SrRNA gene sequencing-based method and we performed Immunohistochemistry (IHC) to detect the activation of inflammatory pathways in endometriosis tissues. We found that in patients with endometriosis, dysbiosis of gut microbiota is associated with patients' stress levels and Paraprevotella, Odoribacter, Veillonell and Ruminococcus show significant differences with reduced levels in chronic stressed endometriosis patients group, which represents a disease-specific change of gut microbiota on the genus level. Besides, compared to the control group, the expression level of inflammatory cytokines, NF-κB p65 and COX-2, increased in the chronic stressed patients group, which means that dysbiosis of gut microbiota may active the inflammatory pathway of gut-brain axis. In conclusion, we found new disease-specific changes of gut microbiota in chronic stressed patients with endometriosis, which can be a new examination target of chronic stress level and may provide an adjuvant therapy method for clinical psychological intervention, reducing the stress level and improving the prognosis of endometriosis patients. Citation Format: Jing Xu, Yu Kang, Yinhua Yu. Dysbiosis of gut microbiota in chronic stressed patients with endometriosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 134.

Effect of chronic heat stress on some physiological and immunological parameters in different breed of broilers.

ABSTRACTThe differences in physiological and immunological parameters and pathological damage to organ tissues exposed to chronic heat stress provide the basis for evaluating heat resistance of different chicken breeds (white recessive rock [WRR] and The Lingshan [LS]). Ninety broilers of each breed were divided equally into a chronic heat stress group and a no heat stress group. The effects of chronic heat stress on the physiological and immunological parameters of broilers were analyzed using flow cytometry, ELISA, RT-qPCR, etc. Under heat stress conditions: (1) H and H/L values were significantly increased (P < 0.01) in the 2 breeds, and were higher in the WRR broilers than in the LS broilers at a late stage (P < 0.05). Although the corticosterone levels were also significantly increased (P < 0.01) in both breeds, they were lower in the 49 d WRR broilers than in the LS broilers (P < 0.01). The number of leukocytes were significantly increased in the 49 d WRR broilers (P < 0.01), whereas the number of CD3+, CD8+ cells, and erythrocytes were significantly reduced (P < 0.05). A significantly (P < 0.01) lower number of CD3+, CD4+ T-lymphocytes, and CD4+/CD8+ were present in WRR compared to that in the LS broilers. (2) The HSP70 transcript was significantly increased in the WRR broilers (P < 0.01), and was higher than the level in the LS broilers. The expression level of HSP70 protein was significantly (P < 0.05) increased in WRR broilers. (3) The WRR broilers developed cardiac and leg muscle inflammatory cellular hyperplasia and local inflammatory lesions, as well as cerebral meningitis and inflammatory hyperplasia of the brain tissue. The LS broilers developed mild cerebral inflammatory hyperplasia and mild inflammatory cellular proliferation in the leg muscle. In conclusion, under heat stress conditions, the relative physiological and immunological parameters were worse in the WRR broilers than in the LS broilers. The WRR broilers showed poor heat tolerance as evidenced from the expression of HSP70 and the extent of histopathological damages.

The role of heat shock protein 70 in oxidant stress and inflammatory injury in quail spleen induced by cold stress.

The aim of this study was to investigate the role of heat shock protein 70 (Hsp70) in oxidative stress and inflammatory damage in the spleen of quails which were induced by cold stress. One hundred ninety-two 15-day-old male quails were randomly divided into 12 groups and kept at 12 ± 1°C to examine acute and chronic cold stress. We first detected the changes in activities of antioxidant enzymes in the spleen tissue under acute and chronic cold stress. The activities of glutathione peroxidase (GSH-Px) fluctuated in acute cold stress groups, while they were significantly decreased (p < 0.05) after chronic cold stress. The activities of superoxide dismutase (SOD), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) content were decreased significantly (p < 0.05) in both of the acute and chronic cold stress groups. Malondialdehyde (MDA) content was significantly increased (p < 0.05) under cold stress except the 0.5h group of acute cold stress. Besides, histopathological analysis showed that quail's spleen tissue was inflammatory injured seriously in both the acute and chronic cold stress groups. Additionally, the inflammatory factors (cyclooxygenase-2 (COX-2), prostaglandin E synthase (PTGES), iNOS, nuclear factor-kappa B (NF-κB), and tumor necrosis factor-a (TNF-α)) and Hsp70 mRNA levels were increased in both of the acute and chronic cold stress groups compared with the control groups. These results suggest that oxidative stress and inflammatory injury could be induced by cold stress in spleen tissues of quails. Furthermore, the increased expression of Hsp70 may play a role in protecting the spleen against oxidative stress and inflammatory damage caused by cold stress.

The impact of chronic stress on the predictors of acute stress-induced eating in women

Chronic stress is associated with palatable food intake and thus, the development of obesity. This may be due to chronic stress disrupting the regulatory effects of the hypothalamic pituitary adrenal (HPA) axis on stress-induced eating. Thus, the primary objective of the current study was to investigate how chronic stress (CS) and cortisol stress reactivity affect eating behaviors following acute stress. Exploratory analyses also sought to determine the distinct psychophysiological factors driving acute stress-induced eating in women with high versus low CS. Women with high (n = 21) and low (n = 14) perceived CS were subjected to the Trier Social Stress task and a rest period on two separate days in order to assess HPA axis and subjective psychological responses to acute stress. Following either stress or rest, participants portioned and consumed snack foods. Women displaying high cortisol reactivity to acute stress ate a smaller percentage of the food they poured than low cortisol reactors, but only in the low CS group. Additionally, stress-induced eating behaviors were associated with cortisol stress reactivity, depressive symptoms, and hunger for women with low CS, but only with a reduction in negative affect for women with high CS. Results indicated that chronic stress may disrupt HPA axis regulation of acute stress-induced consummatory behavior in favor of affective regulation. Replication in women across the weight spectrum may yield a greater understanding of how chronic stress affects the mechanisms underlying acute stress-induced eating, and inform prevention and treatment efforts for conditions related to stress and obesity.

Effect of chronic hypoxia and hypercapnia on learning and memory function in mice and the expression of NT and CGRP in brain

The aim of this study is to investigate the effects of chronic hypoxia and hypercapnia on learning and memory function of mice and the expression of neurotensin (NT) and calcitonin gene–related peptide (CGRP) in mice brain. A total of 30 C57BL/6J male mice were randomly divided into normoxia control group (control group, n = 15) and chronic hypoxia and hypercapnia stress group (experimental group, n = 15). The control group was kept under normal temperature and pressure conditions, while the experimental group was kept in a chamber at normal pressure, hypoxia and hypercapnia for 8 h daily and 6 days a week for 4 weeks. On the 28th day, the learning and memory ability of mice was examined by 8-arm maze. The content of 8-hydroxy-deoxyguanosine (8-OHdG) in brain was detected by enzyme-linked immunosorbent assay (ELISA) analysis. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were determined by spectrophotometry, and the derangement of hippocampal ultrastructures and numbers of apoptotic neurons were observed by microscope. The expression of NT and CGRP in brain tissue was observed by immunochemistry. Compared to control group, the content of 8-OHdG in hippocampal and serum MDA were significantly increased by 1.3 and 1.78 times, while the activity of SOD in serum was decreased by 27.28% in experimental group. Besides, the cellular structure of the hippocampus was disorderly arranged, the shape is irregular and the quantity is markedly reduced obviously in experimental group. In addition, the content of NT and CGRP in brain tissue was higher in experimental group than in control group ( P &lt; 0.05). The stress of chronic hypoxia and hypercapnia not only can induce learning and memory disorders in mice which may be related to increased neuronal apoptosis and oxidative stress injury but also can increase the expression of NT and CGRP in brain tissue which may have some impact on gastrointestinal motility in mice.

Effects of short term low dose melatonin and ketamine on depressive behavior and BDNF expression in rats with chronic stress depression

Objective To evaluate the antidepressant action of melatonin in stress model of depression and the effects of the melatonin on depressive-like behavior. Methods Forty male Wistar rats were randomly divided into four groups(n=10): controls group (CON), chronic unpredictable mild stress group(CUS), chronic unpredictable mild stress group + melatonin group(CUS+ MT) and chronic unpredictable mild stress group + ketamine group(CUS+ KET). The rats in CUS group, CUS+ MT group and CUS+ KET group were given different stress stimulation for 42 days to establish the chronic mild unpredictable stress animal model.Sucrose preference experiments was used to detect the depression model and the level of depression was tested by forced swim test.The influence of Short-term low doses of melatonin on the level of BDNF and GluR1 in the prefrontal cortex, was detected by immunohistochemistry(IHC) on 58 day after the start of the experiment. Results (1) The CUS showed depressant-like behavior, and the percent sucrose uptake scores and the cumulative immobility time of the CUS group were decreased significantly(P<0.05). (2) After injection melatonin 14 d, the cumulative immobility time of CUS+ MT group((60.70±18.56)s) and CUS+ KET group((56.43±20.46)s) were decreased significantly in comparison to the CUS group(146.34±34.10)s). It was observed a highly significant (P<0.05) decrease of and up-regulation of the BDNF cells in CUS+ MT group((1 328.99±282.46)/mm2) and CUS+ KET group((1 224.76±116.53)/mm2) in comparison to the CUS group, the number of BDNF cells in CUS+ MT group was increased significantly in comparison to the CUS+ KET group; (3) After administration drug 14 days, the number of GluR1 cells of CUS+ KET((807.82±153.25)/mm2) but not CUS+ MT((632±156.34)mm2) significantly increased compared with CUS((807.82±193.25)/mm2). Conclusion The results indicate that the melatonin induce an antidepressant-like action like ketamine.The antidepressant effects of melatonin may be related with the level of BNDF. Key words: Melatonin; Ketamine; Depression; Chronic unpredictable mild stress; Rat

Combined corticosterone treatment and chronic restraint stress lead to depression associated with early cognitive deficits in mice.

Many models, such as chronic mild stress, chronic stress or chronic corticosterone injections are used to induce depression associated with cognitive deficits. However, the induction period in these different models is still long and face constraints when it is short such as in the chronic mild stress done in a minimum period of 21days. This study aimed to characterize a model of depression with early onset cognitive deficit. 14days combined chronic injection of corticosterone followed by 2h restraint stress using a restrainer was used to induce depression with early cognitive deficit onset. The forced swim test, sucrose test and plasma corticosterone concentration were used to assess depression-like characteristics. The Morris water maze, novel object recognition task, as well as hippocampal acetylcholinesterase activity were used to assess cognitive deficit. The combined corticosterone injection + chronic restraint stress group presented with marked depression-like behaviour and a higher plasma corticosterone concentration compared to corticosterone injection alone and restraint stress alone. It also showed an alteration in the learning process, memory deficit as well as increased acetylcholinesterase activity compared to corticosterone injection and restraint stress alone groups. These findings suggest that the combined corticosterone administration and chronic restraint stress can be used not only as an animal model for severe depression, but also for depression with early onset cognitive deficit.

Dysbiosis of Gut Microbiota Contributes to Chronic Stress in Endometriosis Patients via Activating Inflammatory Pathway

Background: Gut microbiota can interact with the central nervous system through the gut–brain axis, thus affecting the host's chronic stress level, such as anxiety and depression. Current researches show that patients with endometriosis often have a high level of chronic stress, which will in turn aggravate endometriosis by activating the β-adrenergic signaling pathway. Therefore, we wondered whether the gut microbiota associates with the chronic stress level in endometriosis patients, which may provide new insights on how to improve treatment. Methods: We grouped the endometriosis patients into the chronic stress group and the control group with questionnaires such as generalized anxiety disorder-7 and patient health questionnaire-9 and collected patients' fecal specimens and tissue specimens. Gut microbiota compositions were analyzed by the 16SrRNA gene sequencing-based method, and immunohistochemistry was performed to detect the activation of inflammatory pathways in endometriosis tissues. Results: We found that in patients with endometriosis, the dysbiosis of gut microbiota was associated with their stress levels. Furthermore, the levels of Paraprevotella, Odoribacter, Veillonella, and Ruminococcus were significantly reduced in chronic stressed endometriosis patients, suggestive of a disease-specific change of gut microbiota at the genus level. Compared to the healthy women, the expression levels of inflammatory cytokines, nuclear factor-κB p65, and cyclooxygenase-2 increased in the chronic stressed endometriosis patients, indicating that the dysbiosis of gut microbiota may activate the inflammatory pathway of gut–brain axis. Conclusions: We hypothesized that these new disease-specific changes of gut microbiota in chronic stressed patients with endometriosis may be a new examination target of chronic stress level. These changes may also provide new insights for psychological intervention, thus reducing the stress level and improving the prognosis of endometriosis patients.

Melatonin Improves Learning and Memory Impairment in Chronic Stress Rats

This study aimed to observe the effect of melatonin on chronic stress rats. 60 male rats were randomly divided into five groups: control group (CON group), chronic stress group (CS group), melatonin high dose group (HMT group, 10mg/kg), melatonin middle dose group (MMT group, 5mg/kg), and melatonin low dose group (LMT group, 1mg/kg). Melatonin was daily intragastrically administrated for 4w with stress induction. Ability of spatial learning and memory of rats were determined by morris water maze. Concentration of Ca2+, contents of nitric oxide synthase (NOS) and nitric oxide (NO), and the number of CA3 neurons in hippocampus were tested. Compared with CON group rats, ability of learning and memory were significantly decreased, concentration of Ca2+ and contents of NOS and NO in the hippocampus were significantly increased in CS group rats. The number of CA3 neurons in hippocampus was decreased in CS group rats. As compared with CS group rats, ability of learning and memory were improved in MMT group and LMT group rats, and concentration of Ca2+, contents of NOS and NO in the hippocampus were significantly decreased, and the number of CA3 neurons was decreased in hippocampus. It shows that melatonin improving learning and memory impairment is likely by reducing the calcium and NO in hippocampus.

Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress.

Psychological stress contributes to increased susceptibility to a number of diseases including cancer. The present study was designed to assess the effect of chronic unpredictable stress on N-nitrosodiethylamine induced liver toxicity in terms of in vivo antioxidant status and DNA damage in Swiss albino mice. The animals used in this study were randomized into different groups based on the treatment with N-nitrosodiethylamine or chronic unpredictable stress alone and post-stress administration of N-nitrosodiethylamine. The mice were sacrificed after 12 weeks of treatment, and the status of major enzymatic and non-enzymatic antioxidants, liver function markers, lipid peroxidation and the extent of DNA damage were determined in circulation and liver tissues of all the groups. The N-nitrosodiethylamine treated group showed significantly compromised levels of the antioxidant enzymes, lipid peroxidation, and the liver function markers with enhanced DNA damage as compared to chronic unpredictable stress or control groups. A similar but less typical pattern observed in the chronic unpredictable stress treated mice. All the measured biochemical parameters were significantly altered in the group treated with the combination of chronic unpredictable stress and N-nitrosodiethylamine when compared to controls, or chronic unpredictable stress alone and/or N-nitrosodiethylamine alone treated groups. Thus, exposure to continuous, unpredictable stress conditions even in general life may significantly enhance the hepatotoxic potential of N-nitrosodiethylamine through an increase in the oxidative stress and DNA damage.

Effects of maternal deprivation on stress response and efficacy of escitalopram in adult rats

Objective To investigate the effects of maternal deprivation on chronic stress-induced depression behavior and its characteristics in adult rats, and to evaluate the effects of maternal deprivation on the efficacy of escitalopram. Methods Newborn SD male rats were randomly divided into control(C) group, maternal deprivation (MD) group, chronic unpredictable stress (CUPS) group, maternal deprivation and chronic unpredictable stress (MD+ CUPS) group. Rats in control group received no experimental handling.Rats in MD group and MD+ CUPS group received maternal deprivation from the lst day after birth for 14 days.Rats in CUPS group and MD+ CUPS group received chronic unpredictable stress from 10 th weeks after birth for 28 days. Screened the rats with depression behaviors and treated them with escitalopram for 4 weeks. Results The incidence of anhedonia was significantly different among 4 groups (χ2=143.24, P CUPS group (40.98%) > MD group (17.11%) >C group (4.17%), P<0.0083). The incidence of behavioral despair was significantly different among 4 groups (χ2=70.34, P<0.05). Pairwise comparison showed the incidence of behavioral despair in MD+ CUPS group (43.43%) and CUPS group (39.34%) were significantly higher than that in MD group (13.51%) and C group (3.33%), but no difference was observed between MD+ CUPS and CUPS group (P<0.0083). The incidence of behavioral despair in MD group was significant higher than that in C group. There was no significant efficacy of escitalopram on anhedonia and behavioral despair among 3 stressed models. However the recovery incidence from anhedonia (44/140) was significantly lower than that from behavioral despair (76/140) (χ2=14.93, P<0.05). Conclusion The maternal deprivation increases the stress sensitivity and the incidences of anhedonia in adult rats.The efficacy of escitalopram on behavioral despair is higher than that on anhedonia without influence from maternal deprivation. Key words: Maternal deprivation; Chronic unpredictable stress; Anhedonia; Behavioral despair; Escitalopram

Psychological Stress Alters Extracellular Matrix Metabolism in Mandibular Condylar Cartilage.

To explore the effect of long-term stress on the temporomandibular joint (TMJ) condyle and its possible underlying mechanism. A 12-week, chronic unpredictable mild stress (CUMS) model was used to induce long-term psychological stress in rats. Rats were randomly divided into control group (CONT), chronic unpredictable mild stress group (CUMS) and chronic unpredictable mild stress with fluoxetine treatment group (CUMS + DT) (n = 30 per group). A 5 mg/kg dose of fluoxetine was intraperitoneally injected daily 0.5 h before stress. A sucrose preference test, plasma corticosterone test and open-field test were performed to verify the feasibility of the CUMS model. Histopathology was used to observe the pathological changes of condyle. The expression levels of inflammatory cytokines, matrix metalloproteases (MMPs) and extracellular matrix (ECM) were measured by real-time polymerase chain reaction, western blotting and immunohistochemistry. At 8 and 12 weeks after exposure to CUMS, the rats showed higher plasma corticosterone than the control rats. Additionally, for the open-field test, the rats exposed to CUMS spent more time in the centre zone and moved a shorter distance than the control and drug treatment rats. In addition, pathological changes in the condylar cartilage occurred in the 8-week CUMS subgroup and were more obvious in the 12-week CUMS subgroup. The CUMS caused an increase in the secretion of inflammatory cytokines, imbalanced expression of MMPs and tissue inhibitor of metalloproteinase-1 and accelerated degradation of ECM in condylar cartilage in a time-dependent manner. Osteoarthritis-like lesions can be caused by long-term CUMS in the mandibular condyles, which suggests that the imbalance in chondrocyte-secreted regulatory factors within the cartilage of the TMJ may play an important role in cartilage injury induced by psychological stress.

Pharmacological and biochemical modulation of stress markers by L-NAME and L-Ascorbic acid in chronic restraint model in Wistar rats

Background: Stress is the psycho-physiologic reaction of the body to diverse stimuli including emotional or physical stimuli that imbalance the homeostasis and is also known to trigger various stress markers. Despite the stressors of different types, chronic stress in particular, is known to influence the physiological milieu and breakdown of adaptive mechanisms consequently aggravating the morbid states. Aims and Objectives: The present study was designed to evaluate the modulatory role of stress marker by N-nitro-L-arginine-methyl ester (L-NAME) and L-Ascorbic acid (L-AA) in experimental model of chronic restraint stress (RSx21) in Wistar rats.Materials and Methods: MDA and GSH levels were determined by the method of Okhawa et al 1979 and Ellman 1959 respectively, the SOD and catalase levels were estimated by the method of Nandi and Chatterjee 1988 and Aebi 1984 respectively.Results: Results from our study reveal the significant enhancement of malondialdehyde (MDA) level while significant attenuation of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase levels in chronic stress group compared with vehicle (non-stress) group. The MDA level was found to be increased by L-NAME (10 and 50 mg/kg) in chronic restraint (RSx21) induced rats as compared to vehicle treated RS group. Antioxidant L-AA (100 and 200 mg/kg) significantly reduced MDA level in chronic stress situation. However, L-NAME and L-Ascorbic Acid were found to cause an increase in level of plasma SOD, GSH and catalase when compared with vehicle treated RS group. On the other hand, L-AA (100 and 200 mg/kg) reversed these RS induced changes in these oxidative parameters.Conclusions: Hence, results from the study underlined the intricate role of antioxidants as evidenced by reversal of oxidative stress markers that command a vital role in the development of morbid condition.Asian Journal of Medical Sciences Vol.8(1) 2017 15-20

RU486 Reverses Emotional Disorders by Influencing Astrocytes and Endoplasmic Reticulum Stress in Chronic Restraint Stress Challenged Rats

Aims: To investigate the effect of RU486 (mifepristone) on emotional disorders in chronic restraint stress-induced rats and to explore the mechanisms of that phenomenon. Methods: For this purpose, 80 healthy male Sprague Dawley rats were randomly divided into four groups: the normal group (Con group, The Con group members received no treatment, eating and drinking freely), the chronic restraint stress group (CRS group, normal Sprague Dawley rats treated with chronic restraint stress, 6 h/day for 21days), the propylene glycol group (CRS+propylene glycol) and the RU486 group (CRS+RU486). RU486 or propylene glycol was administered 30 mins before each CRS procedure. Twenty-four hours after CRS exposure, we investigated the effects of CRS on the anxiety-like behavior using an elevated plus-maze (EPM). To explore the mechanisms of RU486 on anxiety, we measured the expression of glial fibrillary acid protein (GFAP) and β-subunit of S100 (S100β) via immunohistochemistry and western blot analysis. Apoptosis was demonstrated by flow cytometry. In addition, endoplasmic reticulum (ER) stress markers, glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and Cysteine aspartic acid specific protease-12 (Caspase-12), were detected by western blot analysis. Results: Compared to the control group, rats in the CRS and propylene glycol group showed decreased exploratory behavior on the open arms during EPM testing, and these reductions were accompanied by significantly reduced GFAP and S100β expression, increased apoptosis and GRP78, CHOP, and caspase-12 expression in the amygdala. However, RU486 increases the exploratory behavior and reverses the changes of GFAP, S100β, GRP78, CHOP, and caspase-12 and protects cells against apoptosis. Conclusions: Taken together, these data suggest that exposure to chronic restraint stress decreases the number of astrocytes and induces apoptosis and ER stress in the amygdala, which are possible causes for psychiatric disorders. RU486 can significantly ameliorate abnormal behaviors in CRS-induced anxiety model rats. The protective effects of RU486 could be attributed to its anti-ER stress, anti-apoptosis and astrocyte increasing effects.