The Study Of Stress-related Depression And Cognition Impairement

Major depression disorder is one of the most common mental disorders, with clinical symptoms such as depression, lower interests and reduced activities. Social functions and quality of lives in patients with depression were severely affected by depression disorder. According to epidemiological study recently, the lifetime prevalence of depression is 10%-15%. The pathogenesis of depression was not clear for now, the imbalance in the neurotransmitter levels, HPA axis dysfunction and brain structure changes may be involved in the pathogenesis of depression. At present, antidepressants were mainly worked based on the hypothesis of monoamine. However, only 60%-70% of the patients were effectively with antidepressant therapy, and suffered from different side effects.Except for the hypothesis of neurotransmitters imbalance, HPA axis dysfunction and brain structural changes, there were also some evidences shown that the cytokines and glucocorticoid were both involved in the pathological process of depression. On the one hand, the association between some somatic diseases and depression has attracted clinical attentions. And depression patients without somatic diseases can also be characterized by elevated inflammation levels in blood, cerebrospinal fluid, or prefrontal cortex. On the other hand, stress is one of the important factors that cause depression. And stress induces direct effect on glucocorticoid level and HPA axis activity. A growing body of evidence indicated that glucocorticoids, abnormal HPA axis activity and damage of glucocorticoid receptor(GR) were key factors in the pathological mechanism of depression. About 50% of the patients with depression have excessive activation of HPA axis.Traumatic events are major stressors in people’s life, which often make the individual produces obvious physiological and psychological stress reaction, and a decline in cognitive function. Traumatic events can have a lasting effect to the brain, and the impact will be delayed to life long time. Cognitive impairment is one of the most common functional damage in depression disorder. The more numbers of depression episodes, the more serious of cognitive impairment. Although the relationship between depression and cognitive impairment is unclear, inflammatory changes are involved in both disorders. Therefore, anti-inflammatory therapy may be a new target of depression and cognitive impairment therapies.Salvianolic acids(Sal) isolated from Radix Salviae miltiorrhizae(Danshen) are water-soluble compounds with well-known anti-inflammatory action. In this study, we discussed the behaviors of depressed rats and related cognitive damage, measured changes of cytokines, glucocorticoid and GR level in brain and explored the effect of salvianolic acid. Then we chose people who experienced Tangshan earthquake during infant or adulthood period to check long term effect of early life stress on cognitive function. Part one Combination therapy of salvianolic acid and fluoxetine improves the cognitive function of rats with chronic stress-induced depressionObjective: To establish the beneficial effects of salvianolic acid and fluoxetine on the improvement of cognitive function and amelioration of depression-like symptoms of rats with chronic stress-induced depression.Methods: Ninety-nine male Sprague-Dawley rats were randomly divided into 5 groups(a control group with no stress challenge and 4 chronic stress groups). Rats assigned to chronic stress groups were exposed to stress for 3 weeks, and then were given placebo, 20mg/kg fluoxetine, 40mg/kg salvianolic acid, or combined fluoxetine and salvianolic acid. Body weight of each rat was recorded along the study. Sucrose preference test(SPT) and water maze experiment were performed after chronic stress challenge and after drug treatment in order to assess the effect of drug treatments on depressive-like symptoms and cognitive function. SPT was also performed before chronic stress exposure for baseline measurement.Results: Exposure of rats to chronic stress for 3 weeks significantly reduced body weight and sucrose preference values comparing to the no stress control. Water maze experiment showed the chronic stress impaired the spatial learning of rats as well(P<0.05). Treatment of stress-challenged rats with fluoxetine and fluoxetine combined with salvianolic acid resulted in shorter training latency, and longer time spent in the target quadrant during exploration stage of water maze experiment comparing placebo treatment. Effect of the combined regimen was found more obvious(P<0.05).The results showed that combination therapy of salvianolic acid and fluoxetine could alleviate depression-like symptoms and cognitive deficit induced by chronic stress.Part two Cytokines, glucocorticoid and GR level Changes in rats with chronic stress-induced depression and the effect of salvianolic acidObjective: To clarify changes of cytokines, glucocorticoid and GR in rats with chronic stress-induced depression,Methods: Thirty eight male Sprague-Dawley rats were randomly divided into 5 groups. 1 n CMS+vehicle(n=8): rats with no stress and treated with vehicle, 2 CMS+vehicle(n=7): rats with stress and treated with vehicle, 3 CMS+Flu(n=8): rats with stress and treated with fluoxetine 20mg/kg, 4 CMS+Sal(n=7): rats with stress and treated with salvianolic acid 40mg/kg, 5 CMS+Flu+Sal(n=8): rats with stress and treated with both fluoxetine 20mg/kg and salvianolic acid 40mg/kg. Prefrontal cortex and hippocampus were removed after 42 days’ stress. Corticosterone and cytokines including IL-1β, IL-2, IL-4, IL-6, IFN-γ and TNF-α were measured. And we also detected Nr3c1 and Fkbp5 m RNA and their protein expression.Results: In prefrontal cortex, IL-1β and TNF-αwere elevated in CMS+vehicle group compared with n CMS+vehicle group(P<0.05). Three weeks after treatment, IL-1β and TNF-α were decreased in CMS+Flu group, CMS+Sal group and CMS+Flu+Sal group(P<0.05) compared with CMS+vehicle group. In hippocampus, IFN-γ and TNF-α were elevated in CMS+vehicle group compared with nCMS+vehicle group(P<0.05). Three weeks after treatment, IFN-γ and TNF-α were decreased in CMS+Flu group, CMS+Sal group and CMS+Flu+Sal group(P<0.05) compared with CMS+vehicle group. Corticosterone in both prefrontal cortex and hippocampus were increased in CMS+vehicle group compared with n CMS+vehicle group(P<0.05). Three weeks after treatment, they were decreased in CMS+Flu group, CMS+Sal group and CMS+Flu+Sal group(P<0.05) compared with CMS+vehicle group. IL-1β level in prefrontal cortex and TNF-α in hippocampus were positive correlated with corticosterone.In prefrontal cortex, Fkbp5 m RNA expression was increased in CMS+vehicle group compared with n CMS+vehicle group(P=0.002). Three weeks after treatment, Fkbp5 m RNA expression was decreased in CMS+Flu group(P<0.001), CMS+Sal group(P<0.001) and CMS+Flu+Sal group(P=0.002) compared with CMS+vehicle group. In hippocampus, there was no significant difference in Fkbp5 m RNA expression among 5 groups(P=0.256).There were no significant differences in Fkbp5 protein among 5 groups in both prefrontal cortex(P=0.706) and hippocampus(P=0.992).In prefrontal cortex and hippocampus, there were no significant differences in GR m RNA expression among 5 groups(P>0.05). Three weeks after treatment, GR m RNA expression in CMS+Sal group was significantly decreased compared with CMS+vehicle group(P<0.05). There were no significant differences in GR protein among 5 groups in both prefrontal cortex(P=0.321) and hippocampus(P=0.664).The above results showed that chronic stress could result in corticosterone and part of pro-inflammatory cytokines in prefrontal cortex(IL-1β and TNF-α) and hippocampus(IFN-γ and TNF-α) increasing after chronic mild stress, and cytokines and cortisol levels were positively correlated. Chronic stress made GR and Fkbp5 m RNA expression level increased, and salvianolic acid and antidepressants fluoxetine can reverse the changes. Part three Cognitive function in adults who experienced Tangshan earthquake in their infancyObjective: To explore cognitive function(working memory and executive function) in adults who experienced Tangshan earthquake in their infancy.Methods: The subjects were recruited from Kailuan Mining Group and Shijiazhuang Steel Plant. According their date and location of birth, people were assigned to 3 groups. Inclusion criteria: 1 Early life Stress group(n=298): Born in Tangshan between July 29, 1975 and April 28, 1976 which means they were exposed to the earthquake between 3 to 12 months of age, 2 Control group 1(n=415): Born in Tangshan between July 29, 1977 and April 28, 1978 which means they were born 1 to 1.9 years after the earthquake, 3 control group 2(n=151): Born in other cities where there is no earthquake during days around July 28, 1976. Exclusion criteria: 1 with organic brain diseases such as Parkinson’s disease, stroke history, 2 depression, schizophrenia, history of mental illness such as acute stress disorder and PTSD, 3 with severe dependence on alcohol or other substances. Childhood trauma questionnaire(CTQ- SF), life events scale(LES), Hopkins words learning tests- revision(HVLT-R), Brief visual memory test-revision(BVMT-R) and Wisconsin card sorting test(WCST) were used to evaluate the early life stress, stress events during adulthood, working memory and executive function.Results: There were no significant differences in CTQ-SF total scores and sub scores, LES total scores and sub scores(P>0.05). Differences in HVLT test 1, test 2 and total scores among 3 groups were not statistically significant(P>0.05). HVLT test 3 score was significant lower than that of control group 2(P=0.001), but was not significant different with that of control group 1(P=0.056). HVLT test 3 score in control 1 was significant lower than that in control group 2(P=0.036). There was no significant difference in BVMT test 1 score(P=0.118). BVMT test 2(P=0.013), test 3(P<0.001) and total scores(P=0.035) were significant different among 3 groups. Pairwise comparisons using post-hoc analysis further showed that BVMT test 2, test 3 and total scores in early life stress group were significant lower than that in control group 1 and control group 2(P<0.05). BVMT test 3 in control 1 group was significant lower than that in control group 2(P=0.014). When come to WCST, we saw Ra, Cc, Re and n Rpe scores were significant lower than that in early life stress group(P<0.05). Pairwise comparisons showed that Ra and Re scores in early life stress group were higher than that in control group 2, and Cc score was significant lower than that in control group 2(P<0.05). Cc and Re scores in early life stress group were significantly lower than that in control group 1(P<0.05).The results indicated that Tangshan earthquake experience during infancy could have long-term effect on individual’s cognitive function especially on spatial memory and executive function. Part four Cognitive function in aged people who experienced Tangshan earthquake in their adulthoodObjective: To explore cognitive function in elder who experienced Tangshan earthquake in their adulthood.Methods: People who experienced Tangshan earthquake in 1976 were included in stress group, and individuals who did not experienced the earthquake were assigned to control group. Mini mental state examination(MMSE) and Montreal cognitive assessment(Mo CA) were administered to all participants.Results: Mo CA and MMSE positive rate in stress group(27.0% and 66.8%) was significant higher than control group(10.3% and 31.5%). MMSE and Mo CA scores in stress group(26.03±4.39 and 22.58±5.51, respectively) were significant lower than control group(27.09±4.14 and 24.58±5.34, respectively). The scores of visual spatial/executive(2.78±1.53), delayed recall(2.12±1.75), recapitulation(0.69±0.46), naming(2.82±0.57) and writing(0.52±0.50) in stress group were significant lower than control group(3.46±1.58, 3.33±1.50, 0.84±0.36, 2.90±0.40 and 0.60±0.49, resectively). There were no significant differences in Mo CA and MMSE positive rate in stress group between male and female. Mo CA positive rate of female in control group was significant higher than male in that group(X2=13.410, P<0.001).The results indicated that experience of Tangshan earthquake in adulthood may induce cognition impairment that continuing to aged years. Women experienced the earthquake may suffer more than men did in cognitive function.Conclusions:1 Combination therapy of salvianolic acid and fluoxetine could alleviate depression-like symptoms and cognitive deficit induced by chronic stress.2 Chronic stress could result in corticosterone and part of pro-inflammatory cytokines in prefrontal cortex and hippocampus increasing after chronic mild stress, and cytokines and cortisol levels were positively correlated. Chronic stress made Fkbp5 m RNA expression level increased, and salvianolic acid and antidepressants fluoxetine can reverse the changes.3 Tangshan earthquake experience during infancy could have long-term effect on individual’s cognitive function especially on spatial memory and executive function.4 Experience of Tangshan earthquake in adulthood may induce cognition impairment that continuing to aged years. Women experienced the earthquake may suffer more than men did in cognitive function.