下丘脑cAMP/PKA/PhK/GP通路在脾气虚食少腹胀中的作用研究

目的:通过观察下丘脑环磷酸腺苷(cyclic adenosine monophosphate, cAMP)/蛋白激酶A(protein kinase, PKA)/磷酸化蛋白激酶(phosphorylase kinase, PhK)/糖原磷酸化酶(glycogen phosphorylase, GP)通路的变化,从中枢糖原分解方面探讨脾气虚食少腹胀发生机制。方法:16只雄性SD大鼠按随机数字表法分为正常组和脾气虚组(模型组)各8只,代谢笼计量大鼠24 h进食水量,炭末推进法检测大鼠的胃残留率和小肠推进率,透射电镜观察下丘脑糖原颗粒情况,ELISA法检测下丘脑ATP、cAMP和PKA水平,Western blot法检测下丘脑PhK和GP表达。结果:与正常组比较,模型组大鼠进食水量减少,胃残留率增加,小肠推进率下降,下丘脑ATP、cAMP和PKA水平下降,下丘脑PhK、GP表达降低,差异有统计学意义。结论:脾气虚食少腹胀与cAMP-PKA-PhK-GP通路抑制所导致的下丘脑能量供给不足有关。     

Prenatal undernutrition increases the febrile response to lipopolysaccharides in adulthood in male rats

It has been reported that prenatal undernutrition affects the development of the peripheral immune system. In this study, the effects of prenatal undernutrition on the febrile response and hypothalamic innate immune system were evaluated in male rats. Pregnant rats were divided into normally nourished (NN) and undernourished groups (UN). The febrile and anorectic responses to lipopolysaccharides (LPS) were evaluated in the offspring of NN and UN dams. The hypothalamic expression levels of pro-inflammatory cytokines, toll-like receptor 4 (TLR4), and neuropeptide Y (NPY) were also evaluated. The UN rats exhibited significantly lighter body weights than the NN rats at birth; however, their mean body weight was the same as that of the NN rats by postnatal day 10. In adulthood, the UN rats exhibited significantly stronger febrile responses than the NN rats, and the anorectic responses of the UN rats also tended to be stronger than those of the NN rats. On the other hand, no differences in hypothalamic interleukin (IL)-1β, IL-6, tumor necrosis factor-α, TLR4, or NPY mRNA expression were detected between the NN and UN rats. These results suggest that prenatal undernutrition has long-lasting effects on the febrile response to LPS. However, the precise mechanism underlying these effects and their pathophysiological significance remain unclear.     

Developmental changes in the hypothalamic mRNA levels of prepro-orexin and orexin receptors and their sensitivity to fasting in male and female rats

Orexin, which is also called as hypocretin (Hcrt), a product of the prepro-orexin (pp-orexin//Hcrt) gene, affects various physiological and behavioral functions, such as the sleep-wake cycle and appetite. The developmental changes in the hypothalamic mRNA levels of pp-prexin and the orexin receptors OX1R and OX2R and their sensitivity to fasting were evaluated in both male and female rats. During development, hypothalamic pp-orexin/Hcrt mRNA expression increased in both male and female rats, whereas hypothalamic OX1R mRNA expression decreased in both sexes. In addition, hypothalamic OX2R mRNA expression increased in male rats, but did not change in female rats. Fasting did not affect hypothalamic pp-orexin/Hcrt mRNA expression in either sex. Hypothalamic OX1R mRNA expression was increased by fasting in the prepubertal period (postnatal days 20 and 30) in female rats, but was not affected by fasting in males. In male rats, hypothalamic OX2R mRNA expression was decreased by fasting during the neonatal period (postnatal day 10), but not the prepubertal period (postnatal days 20 and 30). In females, hypothalamic OX2R mRNA expression was also decreased by fasting; however, the fasting-induced downregulation of hypothalamic OX2R expression persisted until postnatal day 20. These results indicate that the developmental patterns of components of the orexin system and their sensitivity to fasting during the neonatal and prepubertal periods only differ slightly between the sexes. These differences might be involved in the development of some physiological and behavioral functions.     

下丘脑室旁核炎性细胞因子在依普利酮改善心力衰竭中的作用

目的探讨下丘脑室旁核(PVN)炎性细胞因子在依普利酮(EPL)改善心力衰竭中的作用。方法Wistar大鼠分为假手术组(n=6)、模型组(n=10)、吡咯烷二硫基甲酸盐(PDTC)组(n=10)、依普利酮组(n=10)。结扎左冠状动脉前降支诱导急性心肌梗死后心力衰竭,根据分组情况分别给予PDTC[(150 mg/(kg·d)]、依普利酮[30 mg/(kg·d)]和清洁蒸馏水灌胃,假手术组只在相同位置穿线而不结扎。6周后进行血流动力学测定,留取下丘脑、血浆标本,检测PVN内肿瘤坏死因子α(TNF-α)、核因子κB/p65(NF-κB/p65)、促肾上腺皮质激素释放激素(CRH)及血管紧张素Ⅱ(AngⅡ)的表达,并检测血浆TNF-α、去甲肾上腺素(NE)、醛固酮(ALD)水平。结果依普利酮和PDTC干预后大鼠心功能较模型组明显改善。模型组血浆ALD、NE、TNF-α水平显著升高,而依普利酮和PDTC干预后ALD、NE、TNF-α水平降低(P0.05)。模型组PVN内CRH、AngⅡ表达显著增多,依普利酮和PDTC干预后PVN内CRH、AngⅡ表达显著减少(P0.05),NF-κB/p65在依普利酮组和PDTC组的表达较模型组显著降低(P0.05)。依普利酮、PDTC可降低PVN内CRH阳性神经元表达。结论心力衰竭时大鼠PVN内炎性细胞因子表达增多,依普利酮可以改善心力衰竭大鼠心功能,与抑制PVN内炎性细胞因子过表达有关。     

不同体重者下丘脑对葡萄糖耐量试验的反应

目的应用功能核磁共振观察不同体重者下丘脑对口服葡萄糖耐量试验的反应，揭示不同体重者下丘脑中枢糖代谢调节的敏感性与代谢紊乱发生的关系。方法分别采集10名正常体重者与10名肥胖者口服75克葡萄糖后的下丘脑功能磁共振图像数据以及腹部解剖结构图像数据；同时测定受试者的空腹血糖、游离脂肪酸及相应激素水平。应用自行建立的灰度平均值方法进行图像分析处理；同时进行受试者脑功能信号参数与血生化指标水平、相应激素水平及腹部脂肪含量的相关分析。结果不同体重者口服葡萄糖后在下丘脑部位均出现一过性的抑制反应。但肥胖者此抑制反应出现的时间较正常体重者明显延迟；抑制反应强度明显低于正常体重者；抑制反应恢复时间也明显迟于正常体重者。受试者的空腹血浆胰岛素及其瘦素水平与其下丘脑抑制信号恢复到基线的时间有关联；受试者的腹部脂肪含量与其下丘脑抑制信号恢复到基线的时间亦有关联。而受试者空腹血浆葡萄糖、游离脂肪酸水平与其下丘脑功能磁共振采集信号各项参数间没有关联。结论不同体重者下丘脑对糖负荷的中枢反应有所不同，肥胖者下丘脑对糖刺激反应的敏感性有所降低。功能核磁共振是确定脑特定区域功能的一个有效手段。     

Corticosterone mitigates the stress response in an animal model of PTSD

Activation of glucocorticoid receptor signaling in the stress response to traumatic events has been implicated in the pathogenesis of stress-associated psychiatric disorders such as post-traumatic stress disorder (PTSD). Elevated startle response and hyperarousal are hallmarks of PTSD, and are generally considered to evince fear (DSM V). To further examine the efficacy of corticosterone in treating hyperarousal and elevated fear, the present study utilized a learned helplessness stress model in which rats are restrained and subjected to tail shock for three days. These stressed rats develop a delayed long-lasting exaggeration of the acoustic startle response (ASR) and retarded body weight growth, similar to symptoms of PTSD patients (Myers et al., 2005; Speed et al., 1989). We demonstrate that both pre-stress and post-stress administration of corticosterone (3 mg/kg/day) mitigates a subsequent exaggeration of the ASR measured 14 days after cessation of the stress protocol. Furthermore, the mitigating efficacy of pre-stress administration of corticosterone (3 mg/kg/day for three days) appeared to last significantly longer, up to 21 days after the cessation of the stress protocol, in comparison to that of post-stress administration of corticosterone. However, pre-stress administration of corticosterone at 0.3 mg/kg/day for three days did not mitigate stress-induced exaggeration of the ASR measured at both 14 and 21 days after the cessation of the stress protocol. In addition, pre-stress administration of corticosterone (3 mg/kg/day for three days) mitigates the retardation of body weight growth otherwise resulting from the stress protocol. Congruently, co-administration of the corticosterone antagonist RU486 (40 mg/kg/day for three days) with corticosterone (3 mg/kg/day) prior to stress diminished the mitigating efficacy of the exogenous corticosterone on exaggerated ASR and stress-retarded body weight. The relative efficacy of pre versus post administration of corticosterone and high versus low dose of corticosterone on stress-induced exaggeration of innate fear response and stress-retarded body weight growth indicate that exogenous corticosterone administration within an appropriate time window and dosage are efficacious in diminishing traumatic stress induced pathophysiological processes. Clinical implications associated with the efficacy of prophylactic and therapeutic corticosterone therapy for mitigating symptoms of PTSD are discussed, particularly in relation to diminishing hyperarousal and exaggerated innate fear response.     

Impact of aflatoxin B1 on hypothalamic neuropeptides regulating feeding behavior

The presence of mycotoxins in food is a major problem of public health as they produce immunosuppressive, hepatotoxic and neurotoxic effects. Mycotoxins also induce mutagenic and carcinogenic effects after long exposure. Among mycotoxins that contaminate food are aflatoxins (AF) such as AFB1, which is the most powerful natural carcinogen. The AF poisoning results in symptoms of depression, anorexia, diarrhea, jaundice or anemia that can lead to death, but very few studies have explored the impact of AF on neuroendocrine regulations. To better understand the neurotoxic effects of AF related to anorexia, we explored in rat the impact of AFB1 on the major hypothalamic neuropeptides regulating feeding behavior, either orexigenic (NPY, Orexin, AgRP, MCH) or anorexigenic (α-MSH, CART, TRH). We also studied the effect of AFB1 on a novel neuropeptide, the secretogranin II (SgII)-derived peptide EM66, which has recently been linked to the control of food intake. For this, adult male rats were orally treated twice a week for 5 weeks with a low dose (150 μg/kg) or a high dose (300 μg/kg) of AFB1 dissolved in corn oil. Repeated exposure to AFB1 resulted in reduced body weight gain, which was highly significant for the high dose of AF. Immunocytochemical and quantitative PCR experiments revealed a dose-related decrease in the expression of all the hypothalamic neuropeptides studied in response to AFB1. Such orexigenic and anorexigenic alterations may underlie appetite disorders as they are correlated to a dose-dependent decrease in body weight gain of treated rats as compared to controls. We also found a decrease in the number of EM66-containing neurons in the arcuate nucleus of AFB1-treated animals, which was associated with a lower expression of its precursor SgII. These findings show for the first time that repeated consumption of AFB1 disrupts the hypothalamic regulation of neuropeptides involved in feeding behavior, which may contribute to the lower body weight gain associated to AF exposure.     

Different effects of ghrelin, des-acyl ghrelin and obestatin on gastroduodenal motility in conscious rats

Three peptides, ghrelin, des-acyl ghrelin and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. To examine the effects of these peptides, we applied the manometric mea- surement of gastrointestinal motility in freely moving conscious rat models. Ghrelin exerts stimulatory ef- fects on the motility of antrum and duodenum in both fed and fasted state of animals. Des-acyl ghrelin exerts inhibitory effects on the motility of antrum, but not on the motility of duodenum in the fasted state of ani- mals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state, but not in the fasted state of animals. NPY Y2 or Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptors in the brain mediate the action of des-acyl ghrelin, whereas CRF type 1 and type 2 receptors in the brain mediate the action of obestatin. Vagal afferent pathways might be involved in the action of ghre- lin, but not involved in the action of des-acyl ghrelin, whereas vagal afferent pathways might be partially involved in the action of obestatin.     

Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin

BACKGROUND: The question is which hypothalamic systems for food intake might play a role in ethanol intake and contribute to alcohol abuse. The peptide orexin was found to exhibit similar properties to galanin in its relation to dietary fat and may therefore be similar to galanin in having a stimulatory effect on alcohol intake. METHODS: Rats were trained to drink 10% ethanol, implanted with brain cannulas, and then injected in the paraventricular nucleus (PVN), lateral hypothalamus (LH), or nucleus accumbens (NAc) with galanin, orexin-A, and for comparison, ghrelin. Ethanol, food, and water intake were measured at 1, 2, and 4 hours postinjection. RESULTS: In the PVN, both orexin and galanin significantly increased ethanol intake, whereas ghrelin increased food intake. In the LH, orexin again induced ethanol intake, while ghrelin increased eating. In the NAc, orexin failed to influence ethanol intake but did stimulate food intake. CONCLUSIONS: In ethanol-drinking rats, injection of orexin or galanin into the appropriate locus in the hypothalamus induced significant ethanol intake instead of food intake. Ghrelin, as a positive control, failed to influence ethanol intake at the same hypothalamic sites. In the NAc, as an anatomical control, orexin augmented eating but not ethanol intake. Thus orexin and galanin in the hypothalamus selectively stimulated ethanol intake at sites where other studies have shown that both ethanol and fat increase expression of the endogenous peptides. Thus, a neural circuit that evolved with the capability to augment food intake is apparently co-opted by ethanol and may serve as a potential positive feedback circuit for alcohol abuse.     

颅脑损伤合并高钠血症63例临床分析

目的：探讨颅脑损伤后合并高钠血症的临床治疗及高钠血症对预后的影响。方法回顾分析该院2007年1月-2014年12月间收治的重型颅脑损伤合并高钠血症63例患者临床资料,对比血钠高低对死亡率的影响,对比控制尿量组与非控制尿量组血钠恢复时间。结果轻度高钠组、中度高钠组、重度高钠组分别有17例、24例、22例,各组的死亡率分别为29.4%、45.8%、63.6%,轻度高钠组与重度高钠组间相比,差异有统计学意义(P<0.05)。控制尿量组28例,非控制尿量组18例,两组的血钠恢复正常所需的平均天数分别为(4.57±1.86)、(6.38±1.49),两组相比差异有统计学意义(P<0.05)。结论颅脑损伤合并高钠血症血钠值越高,死亡率越高,除常规治疗外,控制尿量可明显缩短血钠恢复的时间。