EFFECTS OF PREPUBERTAL STRESS ON SUBSEQUENT ACTH RESPONSE TO NOVEL STRESS AND CRH IN MALE VS FEMALE RATS

The effects of long-term chronic stress during prepubertal periods of growth and development on an organism's ability to release ACTH during future episodes of an acute novel stress and in response to exogenous CRH were examined. Following a 6-week stress period, in which prepubertal male and female WKY rats were subjected to three different and randomly given stress paradigms (heat, noise and immobilization) at various times of the day (in order to prevent adaptation to stress), chronically stressed male rats were far less able to respond to CRH plus a novel ether stress than were their male controls or their female counterparts. Although baseline ACTH levels were similar in both male and female control and experimental rats, when subjected to a subsequent acute ether stress, the differences in ACTH response between controls and experimentals as well as between males and females were significant. ACTH response to stressors was significantly blunted in both male and female experimental rats compared to their controls, but the male response was significantly lower than that of the females. These results suggest that prepubertal chronic stress may permanently alter an organism's ability to release ACTH, even when subjected to a novel and traumatic ether stress, and that males may be much more susceptible than females to prepubertal stress. Long-term stress, therefore, if experienced during critical developmental periods such as preadolescence, can permanently damage the stress response mechanism and cause other, more serious physiological disorders.     

H-89对坐骨神经结扎大鼠触诱发痛和脊髓背角磷酸化CREB表达的影响

Neuropathicpain(NP)resultingfromvariousetiolo giessharessimilarcharacteristicfeatures :persistentspon taneouspain (burningpain) ,hyperralgesia(exaggeratedpaintonoxiousstimuli)andallodynia(paintoinnocuousstimuli) .NPisanareaoflargelyunmettherapeuticneed .Thecurrentpharmacologicalmainstaysofclinicalmanagementaretricyclicanti depressantsandcertainan ti convulsants ,1buttheseonlyachieveclinicallysignifi cant (greaterthan 5 0 %)painreliefinlessthan 5 0 %ofpatientsandareassociatedwithsub optimalsid…     

丙泊酚对大鼠海马cAMP效应元件结合蛋白磷酸化和cAMP效应元件结合蛋白mRNA表达水平的影响

目的 探讨丙泊酚对大鼠海马cAMP效应元件结合蛋白(cAMP response element binding protein,CREB)磷酸化和CREB mRNA表达水平的影响.方法 成年雄性SD大鼠64只,体重250 g～280 g,采用RandA1.0随机分组软件将实验动物随机分为2组(每组32只),丙泊酚组(P...     

ERK-CREB信号通路在糖皮质激素受体介导大鼠慢性吗啡耐受中的作用

目的 评价细胞外信号调节激酶-cAMP反应元件结合蛋白(ERK- CREB)信号通路在糖皮质激素受体介导大鼠慢性吗啡耐受中的作用.方法 健康雄性SD大鼠,体重280～320 g,月龄2月,经枕骨大孔行鞘内置管.取36只鞘内置管成功的大鼠,采用随机数字表法,将大鼠随机分为6组(n=6):对照组(C组)、慢性吗啡耐受组(M组)、吗啡+地塞米松组(MD组)、吗啡+RU38486组(MR组)、地塞米松组(D组)和RU38486组(R组).分别鞘内注射生理盐水10 μl、吗啡10腭、吗啡10 μg+地塞米松4 μg、吗啡10 μg+ RU38486 2 μg、地塞米松4.μg、RU38486 2 μg,2次、d,连续6d.于给药前1d测定热甩尾潜伏期(TFL)基础值,随后于给药1、3、5d首次给药后30 min及最后1次给药后1 d(T1～4)测定TFL,计算最大镇痛效应百分比(MPE).最后1次测定TEL后取脊髓,采用免疫荧光染色法测定脊髓背角磷酸化ERK(pERK)和磷酸化CREB(pCREB)的表达.结果 与T1时比较,M组和MD组T3.4时MPE降低(P＜0.05).与C组比较,M组MPE升高,脊髓背角pERK和pCREB的表达上调(P＜0.05或0.01),R组和D组上述指标差异无统计学意义(P＞0.05).与M组比较,MR组MPE升高,脊髓背角pERK和pCREB表达上调,MD组脊髓背角pERK和pCREB表达下调,MPE降低(P＜0.05或0.01).结论 糖皮质激素受体介导大鼠慢性吗啡耐受的机制可能与抑制ERK-CREB信号通路有关.     

Investigation of Sex Differences In sIgA Response to the Trier Social Stress Test

Acute stressors can activate the immune system. While many immune system diseases disproportionally affect women, sex differences in adaptive immune response to acute, psychosocial stressors remain to be investigated. The present study tested the hypothesis that female participants experience increased immune response to acute psychosocial stress relative to male participants. Salivary secretory immunoglobulin A (sIgA) was assessed before and after the Trier Social Stress Test (TSST) and at two time points during a recovery period in healthy male (n = 25) and female (n = 24) participants. Exposure to the TSST resulted in significantly increased sIgA that returned to baseline during a subsequent recovery period. Baseline sIgA was higher among women, however, no differences between men and women in response to or recovery from the stressor were observed in the present study. This research describes an initial investigation of sex differences in immune response to acute psychosocial stressors and demonstrates similarity in sIgA response among male and female participants. Copyright © 2016 John Wiley & Sons, Ltd.     

Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury

This study was undertaken to evaluate the effect of simvastatin, a cholesterol-lowering agent, on the Akt-mediated signaling pathway and neurogenesis in the dentate gyrus (DG) of the hippocampus in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into three groups: (1) sham group (n = 8); (2) saline control group (n = 40); and (3) simvastatin-treated group (n = 40). Controlled cortical impact (CCI) injury was performed over the left parietal lobe. Simvastatin was administered orally at a dose of 1 mg/kg starting at day 1 after TBI and then daily for 14 days. Bromodeoxyuridine (BrdU) was injected intraperitoneally into rats. A modified Morris Water Maze (WM) task was performed between 31 and 35 days after treatment to test spatial memory (n = 8/group). Animals were sacrificed at 1, 3, 7, 14, and 35 days after treatment (n = 8/group/time point). Western blot was utilized to investigate the changes in the Akt-mediated signaling pathway. Enzyme-linked immunosorbent assay (ELISA) analyses were employed to measure vascular endothelial growth factor (VEGF) and brain-derived neurotrophin factor (BDNF) expression. Immunohistochemical and fluorescent staining were performed to detect the BrdU- and neuronal nuclei (NeuN)/BrdU-positive cells. Our data show that simvastatin treatment increases phosphorylation of v-akt murine thymoma viral oncogene homolog (Akt), glycogen synthase kinase-3beta (GSK-3beta), and cAMP response element-binding proteins (CREB); elevates the expression of BDNF and VEGF in the DG; increases cell proliferation and differentiation in the DG; and enhances the recovery of spatial learning. These data suggest that the neurorestorative effect of simvastatin may be mediated through activation of the Akt-mediated signaling pathway, subsequently upregulating expression of growth factors and inducing neurogenesis in the DG of the hippocampus, thereby leading to restoration of cognitive function after TBI in rats.     

Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats

While a number of laboratories have begun to examine gender differences in outcome following experimental stroke, little is known about the relative response of male and female brains to traumatic injury. In the following series of experiments, we used the Marmarou impact-acceleration head injury model (with a 500-g, 1.5-m weight drop) to compare the pathophysiological responses of male and female rats to closed-head injury. Cortical blood flow (CBF; laser-doppler flowmetry), mean arterial blood pressure (MAP), blood gas levels, blood pH, and body temperature were measured preinjury and at regular intervals postinjury. Acute survival was assessed 1 h after injury. The role of estrogen in the observed gender differences was assessed by examining these physiological measures after injury in ovariectomized females, with or without 17beta-estradiol replacement, and in intact males, with or without exogenous 17beta-estradiol administration. In the first experiment, significantly more females (100%) survived the acute injury period (60 min) after injury than did males (72%). Survival appeared related to the magnitude and persistence of the posttraumatic drop in MAP. In a second experiment, females showed a less dramatic reduction in and better recovery of CBF than males. The gender difference in CBF was paralleled to some degree by differences in the pattern of MAP changes after injury. Differences in body weight, blood gas levels, or blood pH did not account for the gender difference in CBF. Postinjury CBF was higher in female and male rats given 2 weeks of daily 17beta-estradiol injections prior to injury compared to those given the vehicle only. However, 17beta-estradiol administration did not alter MAP, suggesting that the gender difference in CBF was not strictly due to MAP changes. Our findings suggest that estrogen plays a role in maintaining adequate cerebral perfusion in the acute period following closed-head injury. This protective mechanism may underlie the gender difference in acute survival observed in this study, and may help explain observations of better outcome in females than in males after brain injury. We conclude that CBF preservation is one mechanism by which estrogen is neuroprotective following traumatic brain injury. We hypothesize, based upon known effects of estrogen, that the beneficial microvascular effects of estrogen most likely involve a combination of endothelial nitric oxide synthase induction and an antioxidant effect.     

Distinct effects of acute and chronic nicotine application on microvascular thrombus formation and endothelial function in male and female mice

Background and aims Cigarette smoking is linked to thromboembolic events; however, a relationship between nicotine exposition and thrombosis has not been established. Thus, we intended to study the effect of acute and chronic nicotine application in an in vivo mouse model. Materials and methods In microvessels of the dorsal skin fold chamber, light-dye-induced thrombus formation was analyzed using intravital fluorescence microscopy. Male and female C57BL/6J mice received nicotine chronically via the drinking water (100 μg/ml) for 8 weeks. An additional series of experiments was performed with acute iv nicotine treatment (3 mg/kg body weight). Results No significant differences in microvascular thrombus formation were detected after chronic nicotine application in male and female animals when compared with controls. Accordingly, flow cytometric analysis did not show significant effects on platelet activity. Chronic nicotine treatment resulted in a significantly reduced endothelial activation in male, but not in female mice. In contrast, acute iv application of nicotine revealed significantly shorter thrombosis times in arterioles of female mice and a significantly increased endothelial P-selectin expression in mice of both genders. Conclusion Chronic nicotine application does not promote microvascular thrombus formation in mice of either gender, whereas acute high-dose iv administration caused a significant increase of arteriolar thrombosis in female animals probably via a synergistic effect of increased endothelial P-selectin expression and female hormone levels. A gender-dependency of acute nicotine action can be presumed. Best abstracts — Surgical Forum 2007     

多次异丙酚给药对大鼠海马pCREB表达的影响

目的 探讨多次异丙酚给药对大鼠海马磷酸化环磷酸腺苷反应元件结合蛋白(pcREB)表达的影响.方法 雄性Wistar大鼠48只,日龄18～21 d,体重40～60 g,随机分为4组,每组12只,各组分别腹腔注射0.9%生理盐水10 ml/ks(A组)、异丙酚50 mg/kg(B组)、异丙酚100 mg/kg(C组)或异丙酚200 mg/kg(D组),连续用药5 d.每天均采用Morris水迷宫实验测试大鼠空间学习记忆能力.第5天测试结束后处死大鼠取脑分离海马组织,每组随机取6只应用免疫组织化学法检测海马pCREB的表达,剩余6只透射电镜下观察海马神经元突触结构.结果 与第1天比较,各组第4、5天逃避潜伏期明显缩短(P<0.05);与A组比较,其余3组第4、5天逃避潜伏期延长(P<0.05);与B组比较,D组第5天逃避潜伏期延长(P<0.05);与A组和B组比较,c组和D组海马pCREB表达下调(P<0.05).随异丙酚剂量增加,大鼠海马神经元突触结构受损加重.结论 多次较大剂量异丙酚给药可引起幼年大鼠空间学习记忆能力降低,其机制可能与海马pCREB表达下调、海马神经元突触结构改变有关.     

Gender affects macrophage cytokine and prostaglandin E2 production and PGE2 receptor expression after trauma

BACKGROUND: Gender influences morbidity and mortality after injury. Hormonal differences are important; however, the role of prostaglandins as mediators in immune dysfunction relating to gender differences after trauma is unclear. We hypothesized that gender-dependent differences in PGE(2) receptor expression and signaling may be involved in immune-related differences. This study determined prostaglandin receptor subtype (EP1-EP4) expression following injury and determined whether gender differences influence EP receptor expression. MATERIALS AND METHODS: BALB/c male and female mice (estrus and pro-estrus) (n = 6 per group) were subjected to femur fracture and 40% hemorrhage (trauma) or sham injury (anesthesia). Seven days later, the splenic macrophages were harvested and stimulated with lipopolysaccharide (Escherichia coli serotype O55:B5). After 6 h mRNA samples were collected for EP receptor mRNA expression and at 24 h supernatants were collected for PGE(2), TNF-alpha, and IL-6 production. RESULTS: The expression of EP2-4 receptors was higher in female pro-estrus mice compared with male mice. EP1 receptor expression was higher in males than pro-estrus females. There was decreased expression of all four receptors after trauma in female estrus compared with control estrus mice. Macrophage PGE(2), TNF-alpha, and IL-6 production was significantly increased in injured female mice compared with female controls but there were no differences in injured male mice compared with male controls. PGE(2) and TNF-alpha production by traumatized male mice were significantly less than that produced by traumatized pro-estrus females. CONCLUSIONS: These data suggest gender-related differences in response to traumatic injury and that alterations in specific EP receptor subtypes may be involved in immune dysfunction after injury. Studies to evaluate targeted modulation of these receptor subtypes may provide further insights to gender-specific differences in the immune response after injury.     

Effect of immobilization stress on testosterone and inhibin in male rats

Adult male Wistar rats were subjected to acute and chronic immobilization stress. Changes in plasma levels of LH, FSH and testosterone and in the content of testicular inhibin and testosterone were studied. Plasma LH levels decreased significantly in response to both acute and chronic stress. Significant decreases in plasma testosterone content were also observed after chronic stress. In contrast, plasma FSH and testicular bioassayable inhibin content did not change after acute or chronic stress. These findings indicate that in male rats immobilization stress induced a dissociation in LH and FSH responses, and decreased testosterone while inhibin remained unaffected.     

Occupational stress and gender: a cross‐cultural study

The aim of this study was to examine the interaction of gender and culture in managers' experiences of work stress. Data were collected on sources of occupational stress (stressors), coping and consequences of occupational stress (strains) from male and female managers from four countries—South Africa, the United Kingdom, United States of America and Taiwan. Few significant results were found for the interaction between country and gender on any of the measures. When the sample as a whole was examined, however, there were also virtually no differences in sources of work stress, but there were differences in the consequences of work stress for male and female managers. The implications of finding a lack of differences in sources of work stress for males and females combined with finding differences in strains for male and female managers are discussed. Copyright © 2000 John Wiley & Sons, Ltd.     

Brain oxygenation and metabolism during selective cerebral perfusion in neonates.

OBJECTIVE: To investigate the possible neuroprotective effects of selective cerebral perfusion (SCP) during deep hypothermic circulatory arrest on brain oxygenation and metabolism in newborn piglets. METHODS: Newborn piglets 2-4 days of age, anesthetized and mechanically ventilated, were used for the study. The animals were placed on cardiopulmonary bypass, cooled to 18 degrees C and put on SCP (20 ml/(kg min)) for 90 min. After rewarming, the animals were monitored through 2h of recovery. Oxygen pressure in the microvasculature of the cortex was measured by oxygen-dependent quenching of phosphorescence. The extracellular level of dopamine in striatum was measured by microdialysis and hydroxyl radicals by ortho-tyrosine levels. Levels of phosphorylated cAMP response element binding protein (pCREB) in striatal tissue were measured by Western blots using antibodies specific for phosphorylated CREB. The results are presented as mean+/-SD (p<0.05 was significant). RESULTS: Pre-bypass cortical oxygen pressure was 48.9+/-11.3 mmHg and during the first 5 min of SCP, the peak of the histogram, corrected to 18 degrees C, decreased to 11.2+/-3.8 mmHg (p<0.001) and stayed near that value to the end of bypass. The mean value for the peak of the histograms measured at the end of SCP was 8+/-3 mmHg (p<0.001). SCP completely prevented the deep hypothermic circulatory arrest-dependent increase in extracellular dopamine and hydroxyl radicals. After SCP, there was a statistically significant increase in pCREB immunoreactivity (534+/-60%) compared to the sham-operated group (100+/-63%, p<0.005). Measurements of total CREB showed that SCP did induce a statistically significant increase in CREB as compared to sham-operated animals (168+/-31%, p<0.05). CONCLUSION: SCP, as compared to DHCA, improved cortical oxygenation and prevented increases in the extracellular dopamine and hydroxyl radicals. The increase in pCREB in the striatum following SCP may contribute to improved cellular recovery after this procedure.     

Unveiling gender differences in demand ischemia: a study in a rat model of genetic hypertension.

OBJECTIVE: Female gender is associated with reduced tolerance against acute ischemic events and a higher degree of left ventricular hypertrophy under chronic pressure overload. We tested whether female and male rats with left ventricular hypertrophy present the same susceptibility to demand ischemia. METHODS: Hearts from hypertrophied female and male salt-resistant and salt-sensitive Dahl rats (n=8 per group) underwent 30min of demand ischemia induced by rapid pacing (7Hz) and an 85% reduction of basal coronary blood flow, followed by 30min of reperfusion on an isovolumic red cell perfused Langendorff model. RESULTS: In female hearts, high-salt diet induced a pronounced hypertrophy of the septum (2.38+/-0.09 vs 2.17+/-0.08mm; p<0.01), whereas male hearts showed the greatest increase in the anterior/posterior wall of the left ventricle (LV) (3.19+/-0.22 vs 2.01+/-0.16mm; p<0.05) compared with salt-resistant controls. At baseline, LV-developed pressure/g LV was significantly higher in female than male hearts (200+/-13 and 196+/-14 vs 161+/-10 and 152+/-15mmHgg(-1); p<0.01), independent of hypertrophy, indicating greater contractility in females. During ischemia, LV-developed pressure decreased in all groups; at the end of reperfusion, hypertrophied female and male hearts showed higher developed pressures independent of gender (148+/-3 and 130+/-8 vs 100+/-7 and 85+/-6mmHg; p<0.01). In contrast, diastolic pressure was more pronounced in female than in male hypertrophied hearts during ischemia and reperfusion (24+/-3 vs 12+/-2mmHg; p<0.01). CONCLUSIONS: In the pressure overload model of the Dahl salt-sensitive rat, female gender is associated with a more pronounced concentric hypertrophy, whereas male hearts develop a more eccentric type of remodeling. Although present at baseline, after ischemia/reperfusion systolic function is gender-independent but more determined by hypertrophy. In contrast, diastolic function is gender-dependent and aggravated by hypertrophy, leading to pronounced diastolic dysfunction. We can conclude that in the malignant setting of demand ischemia/reperfusion gender differences in hypertrophied hearts are unmasked: female hypertrophied hearts are more susceptible to ischemia/reperfusion than males. To determine whether in female hypertensive patients with acute coronary syndromes, diastolic dysfunction could contribute to the worse clinical course, further experimental and clinical studies are needed.     

p38MAPK信号转导通路在大鼠骨癌痛中的作用

目的 探讨p38丝裂原活化蛋白激酶(p38MAPK)信号转导通路在大鼠骨癌痛中的作用.方法 雌性sD大鼠56只,体重150～170 g,随机分为4组(n=14):生理盐水对照组(NS组)、骨癌痛组(BC组)、二甲基亚砜组(DMSO组)和p38MAPK抑制剂组(SB203580组).骨髓腔内注射Walker256细胞悬液制备大鼠骨癌痛模型,注射后10 d,DMSO组和SB203580组分别鞘内注射5%二甲基亚砜和SB203580(10 μg)10 μl.各组随机取8只大鼠,于注射Walker256细胞悬液前、注射后1、3、5、7、10 d,鞘内给药后1、3、6、12、24 h时采用von Frey纤维丝测定术侧后爪机械缩足反射阈值(MWT);各组余6只大鼠鞘内给药后6 h时取L_(4,5)脊髓,采用免疫组化法检测脊髓背角磷酸化环磷酸腺苷反应元件结合蛋白(pCREB)的表达水平.结果 骨髓腔内注射Walker256细胞悬液后7 d大鼠术侧后爪MWT开始降低,鞘内注射SB203580提高了MWT;骨髓腔内注射Walker256细胞悬液后脊髓背角pCREB表达上调,鞘内注射SB203580后脊髓背角pCREB表达下调.结论 鞘内注射SB203580可通过抑制脊髓背角pCREB的表达减轻骨癌痛;p38MAPK信号转导通路在骨癌痛中起重要作用.     

Opposite effects of testosterone and estrogens on chronic allograft nephropathy

In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of chronic allograft nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in allografts of both genders that paralleled a decreased mRNA expression of TGF-beta1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on chronic allograft nephropathy.     

柴胡皂苷A通过cAMP/CREB信号通路对脑损伤大鼠认知功能的影响

目的观察柴胡皂苷A(SSA)对创伤性脑损伤大鼠认知功能及海马组织内cAMP/CREB信号通路及其调控的脑源性神经生长因子(BDNF)表达的影响。方法成年雄性SD大鼠60只,体重360~400g,随机分为假手术组(S组)、创伤组(T组)和创伤加SSA组(A组)。创伤后每天腹腔注射5mg/kg SSA(A组)或等容量生理盐水(S组、T组),连续5d。于创伤后1、3、7、14d,采用Morris水迷宫检测大鼠潜伏期和游泳距离;末次行为学测试后处死大鼠,采用ELISA法测定海马组织中BDNF和cAMP浓度,采用Western blot检测环磷酸腺苷反应元件结合蛋白(CREB)和磷酸化的环磷酸腺苷反应元件结合蛋白(pCREB)浓度。结果创伤后1、3、7、14dT组和创伤后1、3dA组大鼠潜伏期和游泳距离明显长于S组(P0.05);创伤后7、14dA组大鼠潜伏期和游泳距离明显短于T组(P0.05);T组BDNF、cAMP、CREB及pCREB浓度明显低于S组(P0.05);A组BDNF、cAMP、CREB及pCREB浓度明显高于T组(P0.05)。结论 SSA能够明显改善创伤性脑损伤大鼠认知功能,其机制可能与其激活cAMP/CREB信号通路及上调BDNF的表达有关。     

Ⅰ组代谢型谷氨酸受体拮抗药AIDA对吗啡耐受大鼠脊髓pCREB表达的影响

目的 观察Ⅰ组代谢型谷氨酸受体拮抗药AIDA对吗啡耐受大鼠脊髓背角磷酸化环腺苷酸反应元件结合蛋白(pCREB)表达的影响.方法 24只雄性SD大鼠,随机均分为四组:吗啡耐受组(M组)、AIDA组(A组)、吗啡加AIDA组(MA组)和对照组(C组).每组连续给药8 d,每天2次.行为学上测定大鼠甩尾潜伏期(TFL)观察大鼠吗啡耐受情况,根据公式计算最大镇痛效应百分比(MPE%).8d后处死动物,采用Western blot方法测定并比较每组脊髓背角蛋白pCREB表达量.结果 第1、2天M组和MA组MPE%明显高于C组(P＜0.01),但随着用药天数增加,M组的MPE%逐渐下降,第7天后与C组比较差异无统计学意义.用药后第3至第8天MA组MPE%显著高于M组(P＜0.01).MA组各时点MPE%均显著高于A组和C组(P＜0.01).M组脊髓背角pCREB表达量明显高于其他三组(P＜0.01).MA组pCREB表达量亦较C组和A组升高(P＜0.05).结论 吗啡耐受时pCREB表达上调.AIDA可以延缓吗啡耐受形成,其机制与抑制pCREB表达有关.