Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state.     

Nitric Oxide Participates in the Brain Ischemic Tolerance Induced by Intermittent Hypobaric Hypoxia in the Hippocampal CA1 Subfield in Rats

Previous studies have shown that intermittent hypobaric hypoxia (IH) preconditioning protected neurons survival from brain ischemia. However, the mechanism remains to be elucidated. The present study explored the role of nitric oxide (NO) in the process by measuring the expression of NO synthase (NOS) and NO levels. Male Wistar rats (100) were randomly assigned into four groups: sham group, IH?+?sham group, ischemia group and IH?+?ischemia group. Rats for IH preconditioning were exposed to hypobaric hypoxia mimicking 5000 m high-altitude (P_B?=?404 mmHg, PO₂?=?84 mmHg) 6 h/day, once daily for 28 days. Global brain ischemia was established by four-vessel occlusion that has been created by Pulsinelli. Rats were sacrificed at 7th day after the ischemia for neuropathological evaluation by thionin stain. In addition, the expression of neuronal NOS (nNOS), inducible NOS (iNOS), and NO content in the hippocampal CA1 subfield were measured at 2nd day and 7th day after the ischemia. Results revealed that global brain ischemia engendered delayed neuronal death (DND), both nNOS and iNOS expression up-regulated, and NO content increased in the hippocampal CA1 subfield. IH preconditioning reduced neuronal injury induced by the ischemia, and prevented the up-regulation of NOS expression and NO production. In addition, l-NAME?+?ischemia group was designed to detect whether depressing NO production could alleviate the DND. Pre-administration of l-NAME alleviated DND induced by the ischemia. These results suggest that IH preconditioning plays a protective role by inhibiting the over expression of NOS and NO content after brain ischemia.     

Effect of Homocysteine on Bone Mineral Density of Rats

The relationship between plasma levels of homocysteine (Hcy) and femur bone mineral density (BMD) was studied in Wistar rats. After 8 weeks of treatment with 0.5 and 1.0 g kg⁻¹ day⁻¹ l-methionine the mean plasma levels of Hcy were 7.67 ± 1.25 and 61.2 ± 11.4 μmol/l, respectively. Only rats treated with the higher dose had Hcy levels significantly higher than those of controls, 6.38 ± 0.90 μmol/l (p < 0.001). Dual Energy X-ray Absorptiometry was used to measure the BMD, which was significantly lower only in the animals with the highest plasma levels of Hcy (p < 0.001). This led us to conclude that increased levels of Hcy are associated with risk of decreased BMD.     

慢性间歇低压低氧暴露对小鼠空间记忆及海马谷氨酸受体磷酸化 水平的影响

目的:观察慢性间歇低压低氧暴露对成年C57小鼠认知功能、海马区p-Glu R-831、845位点蛋白表达以及海马区突触囊泡释放的影响。方法:雄性C57小鼠,随机分为对照组(n=16)与暴露组(n=16)。暴露组给予每天6 h 5000 m低压低氧暴露,持续4w;对照组无低压低氧暴露。两组小鼠其他饲养条件一致。利用Morris水迷宫实验检测每组小鼠空间记忆能力;免疫印迹实验检测Glu R1蛋白ser831和ser845位点磷酸化水平变化;透射电镜实验观察低氧对突触囊泡的影响。结果:(1)水迷宫结果显示慢性间歇低压低氧暴露后,暴露组平均逃脱潜伏期(17.6±1.69 s)显著低于对照组(27.3±1.45 s),暴露组小鼠平台搜索能力提升;(2)免疫印迹结果显示,暴露组小鼠海马Glu R1蛋白ser831和ser845位点磷酸化水平显著高于对照组小鼠;(3)透射电镜结果显示,暴露组小鼠海马区突触囊泡数目显著多于对照组,且差异有统计学意义。结论:慢性间歇低压低氧暴露可以显著提升C57小鼠空间认知功能,其机制可能是通过增加Glu R1蛋白ser831和ser845位点磷酸化水平,并增加突触结构内囊泡数目。     

Role of Nitric Oxide Synthase in the Infarct-Limiting Effect of Normobaric Hypoxia

Journal of Evolutionary Biochemistry and Physiology - The study was carried out in male Wistar rats. Animals were randomly divided into normoxic control groups and groups exposed to normobaric...     

The Role of Preventing Nitric Oxide Deficiency in the Antihypertensive Effect of Adaptation to Hypoxia

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. The adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5–6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate that the correction of endothelial NO deficiency plays a significant role in the antihypertensive effect of adaptation to hypoxia.     

去卵巢骨质疏松症大鼠模型骨密度的变化

观察3月龄SD雌鼠切除双侧卵巢29周内模型组和雌二醇组动物第三腰椎及股骨骨密度的变化,同时与假手术组比较。结果表明,SD雌性大鼠切除卵巢9周股骨骨密度明显低于假手术组(P<001),13周后腰椎骨骨密度也有显著差异(P<001),29周内模型稳定。皮下注射苯甲酸雌二醇40μgkg×2次周,在12周能够明显提高切卵巢SD大鼠的股骨骨密度并使其接近正常,16周后第三腰椎的骨密度也能够明显提高。切卵巢骨质疏松症大鼠模型治疗性给药需要大约9～13周左右模型才能成功,切除卵巢后29周内模型仍然稳定。     

羊骨酶解发酵液钙鳌合物对骨质疏松大鼠骨密度和骨代谢生化指标的影响

目的探讨羊骨酶解发酵液钙螯合物（SBEF-Ca）对雌激素缺乏造成的骨质疏松的防治作用。方法 40只3.5月龄的Sprague-Dawley大鼠,按体重随机分为正常组（假手术＋蒸馏水）、模型对照组（去卵巢＋蒸馏水）和高、中、低3个剂量组（去卵巢＋SBEF-Ca）。术后12 d,持续灌胃11周后,测定股骨密度、长度以及血清中反映骨代谢的主要生化指标。结果模型对照组大鼠股骨密度和长度显著减小,各剂量组均可扭转这种减小趋势并使股骨密度和长度维持在正常组水平,其中高剂量组的股骨密度显著大于中、低剂量组;各剂量组的股骨长度差异不显著;所有大鼠的血Ca、血P水平差异无显著性;模型对照组的血清碱性磷酸酶（ALP）、骨钙素（BGP）水平明显升高,而各剂量组的ALP、BGP水平与正常组差异不显著,且高剂量组ALP水平显著低于中、低剂量组,中、高剂量组的BGP水平（P〉0.05）显著低于低剂量组。结论低、中、高剂量的SBEF-Ca对绝经后骨质疏松症有预防作用。     

降钙素对骨质疏松大鼠骨密度形态计量学与骨代谢的影响

目的探讨降钙素(密盖息)对骨质疏松大鼠骨密度、骨形态计量学影响以及与血钙、磷、维生素D代谢和生长因子的关系。方法用摘除大鼠双侧卵巢的方式制备骨质疏松模型(OVX),实验动物分为4个组:模型对照组、密盖息治疗组,盐酸雷洛昔芬治疗组,假手术组。应用HOLOGIC第4代双能X线4500W骨密度仪测定大鼠腰椎、股骨上段骨密度值(BMD);以骨形态计量学测股骨骨小梁面积、矿化沉积率;用ELISA法测定血清IGF-1水平和血清25OHVitD浓度以及血淋巴细胞维生素D受体(VDR)含量。结果密盖息治疗组、盐酸雷洛昔芬治疗组均较OVX组腰椎、股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。密盖息治疗组较盐酸雷洛昔芬治疗组股骨上段骨密度增高,两组之间差异有显著性(P<0.01)。密盖息治疗组骨小梁面积明显增加、矿化沉积率增高。密盖息治疗组、盐酸雷洛昔芬治疗组血清IGF-1浓度值、血清25-OHVitD浓度值升高,与OVX组比较差异有显著性(P<0.01)。各组血淋巴细胞VDR含量无明显变化,与OVX组比较差异无显著性(P>0.05)。结论密盖息能够预防腰椎、股骨上段骨密度丢失,使骨小梁面积明显增加、矿化沉积率增高并且血清IGF-1及血清25-OHVitD浓度值升高,但对VDR含量无明显作用。     

Intermittent Hypobaric Hypoxia Preconditioning Induced Brain Ischemic Tolerance by Up-Regulating Glial Glutamate Transporter-1 in Rats

Several studies showed that the up-regulation of glial glutamate transporter-1 (GLT-1) participates in the acquisition of brain ischemic tolerance induced by cerebral ischemic preconditioning or ceftriaxone pretreatment in rats. To explore whether GLT-1 plays a role in the acquisition of brain ischemic tolerance induced by intermittent hypobaric hypoxia (IH) preconditioning (mimicking 5,000?m high-altitude, 6?h per day, once daily for 28?days), immunohistochemistry and western blot were used to observe the changes in the expression of GLT-1 protein in hippocampal CA1 subfield during the induction of brain ischemic tolerance by IH preconditioning, and the effect of dihydrokainate (DHK), an inhibitor of GLT-1, on the acquisition of brain ischemic tolerance in rats. The basal expression of GLT-1 protein in hippocampal CA1 subfield was significantly up-regulated by IH preconditioning, and at the same time astrocytes were activated by IH preconditioning, which appeared normal soma and aplenty slender processes. The GLT-1 expression was decreased at 7?days after 8-min global brain ischemia. When the rats were pretreated with the IH preconditioning before the global brain ischemia, the down-regulation of GLT-1 protein was prevented clearly. Neuropathological evaluation by thionin staining showed that 200?nmol DHK blocked the protective role of IH preconditioning against delayed neuronal death induced normally by 8-min global brain ischemia. Taken together, the up-regulation of GLT-1 protein participates in the acquisition of brain ischemic tolerance induced by IH preconditioning in rats.     

自噬对慢性间歇性低氧大鼠颏舌肌损伤的作用及机制

目的:探讨自噬在慢性间歇性低氧状态下大鼠颏舌肌损伤中的作用及其机制。方法:将36只SD大鼠随机均分为对照组,慢性间歇性低氧组(chronic intermittent hypoxia,CIH组),慢性间歇性低氧+氯喹组(CIH+CQ组)。苏木素-伊红(HE)染色观察颏舌肌组织形态学变化;激光共聚焦显微镜下观察自噬标记物LC3在颏舌肌中的表达;免疫组织化学染色法观察组织中细胞色素c(cytochrome,Cyt c)的表达。结果:激光共聚焦结果显示,对照组颏舌肌中未见明显LC3表达,CIH组中LC3的平均荧光强度较对照组明显增强(P0.05),CIH+CQ组中LC3的平均荧光强度较CIH组显著增加(P0.05)。免疫组织化学结果显示:CIH组中Cyt c的阳性表达较对照组增加(P0.05),CIH+CQ组中Cyt c表达与CIH组相比显著增加(P0.05)。结论:慢性间歇性低氧引起颏舌肌线粒体损伤,触发细胞凋亡,同时诱发自噬。抑制自噬加重线粒体损伤,促进细胞凋亡。说明自噬可能通过抑制凋亡而在慢性间歇性低氧状态下的大鼠颏舌肌中起维护肌肉功能的作用。     

Effects of Aluminum Exposure on Bone Mineral Density,Mineral, and Trace Elements in Rats

The purpose of the study was to investigate the effects of aluminum (Al) exposure on bone mineral elements, trace elements, and bone mineral density (BMD) in rats. One hundred Wistar rats were divided randomly into two groups. Experimental rats were given drinking water containing aluminum chloride (AlCl₃, 430 mg Al³⁺/L), whereas control rats were given distilled water for up to 150 days. Ten rats were sacrificed in each group every 30 days. The levels of Al, calcium (Ca), phosphorus (P), magnesium (Mg), zinc (Zn), iron (Fe), copper (Cu), manganese (Mn), selenium (Se), boron (B), and strontium (Sr) in bone and the BMD of femur were measured. Al-treated rats showed lower deposition of Ca, P, and Mg compared with control rats. Levels of trace elements (Zn, Fe, Cu, Mn, Se, B, and Sr) were significantly lower in the Al-treated group than in the control group from day 60, and the BMD of the femur metaphysis in the Al-treated group was significantly lower than in the control group on days 120 and 150. These findings indicate that long-term Al exposure reduces the levels of mineral and trace elements in bone. As a result, bone loss was induced (particularly in cancellous bone).     

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

Brief limb ischemia was reported to protect neurons against injury induced by subsequent cerebral ischemia-reperfusion, and this phenomenon is known as limb ischemic preconditioning (LIP). To explore the role of nitric oxide (NO) in neuroprotection of LIP in rats, we observed changes in the content of nitric oxide (NO) and activity of NO synthase (NOS) in the serum and CA1 hippocampus of rats after transient limb ischemic preconditioning (LIP), and the influence of N^G-nitro-l-arginine methylester (l-NAME), a NOS inhibitor, on the neuroprotection of LIP against cerebral ischemia-reperfusion injury. Results showed that NO content and NOS activity in serum increased significantly after LIP compared with the sham group. The increase showed a double peak pattern, in which the first one appeared at time 0 (immediate time point) and the second one appeared at 48 h after the LIP (P < 0.01). The NO content and NOS activity in the CA1 hippocampus in LIP group showed similar change pattern with the changes in the serum, except for the first peak of up-regulation of NO content and NOS activity appeared at 6 h after LIP. Pretreatment with l-NAME before LIP blocked the neuroprotection of LIP against subsequent cerebral ischemic insult. The blocking effect of l-NAME was abolished with pretreatment of l-Arg. These findings indicated that NO may be associated with the tolerance of pyramidal cells in the CA1 hippocampus to ischemia induced by LIP in rats.     

低压低氧对氧化-抗氧化系统的影响

低压低氧引起机体各组织器官的病理生理变化,其中氧化应激损伤是大多数疾病的病理生理基础。大量研究发现,低压低氧导致机体内抗氧化酶水平降低,而脂质过氧化终产物丙二醛水平升高,表明低压低氧加重机体的氧化应激损伤。本文描述急性低压低氧暴露以及间歇性低压低氧预处理对氧化-抗氧化系统的影响,并阐述世居高原人群的高原适应性,就不同类型低压低氧对机体氧化-抗氧化系统的影响作一综述。急性低压低氧不仅影响抗氧化酶活性,而且具有抑制抗细胞凋亡蛋白,促进缺氧细胞凋亡的作用,影响氧化-抗氧化系统的平衡。而间歇性慢性低压低氧预处理则对组织器官具有保护作用,为治疗心血管疾病提供了一条非药物治疗的可能途径。     

Plasma Copper and Bone Mineral Density in Osteopenia: An Indicator of Bone Mineral Density in Osteopenic Females

Copper concentrations in blood plasma have been determined in 25 osteopenic females using inductively coupled plasma–mass spectrometry. A high degree of correlations has been demonstrated between the copper concentrations in plasma and the bone mineral density of the lumbar spine as measured using dual energy X-ray absorptiometry and quantitative computerized tomography. Results clearly indicate the involvement of copper in bone health and osteopenia. It is further suggested that plasma copper might be useful as a cheap and simple method indicative of bone mineral density in osteopenic postmenopausal females.     

The Effect of HIV-Hepatitis C Co-Infection on Bone Mineral Density and Fracture: A Meta-Analysis

Objective

There is a variable body of evidence on adverse bone outcomes in HIV patients co-infected with hepatitis C virus (HCV). We examined the association of HIV/HCV co-infection on osteoporosis or osteopenia (reduced bone mineral density; BMD) and fracture.

Design

Systematic review and random effects meta-analyses.

Methods

A systematic literature search was conducted for articles published in English up to 1 April 2013. All studies reporting either BMD (g/cm², or as a T-score) or incident fractures in HIV/HCV co-infected patients compared to either HIV mono-infected or HIV/HCV uninfected/seronegative controls were included. Random effects meta-analyses estimated the pooled odds ratio (OR) and the relative risk (RR) and associated 95% confidence intervals (CI).

Results

Thirteen eligible publications (BMD N = 6; Fracture = 7) of 2,064 identified were included with a total of 427,352 subjects. No publications reported data on HCV mono-infected controls. Meta-analysis of cross-sectional studies confirmed that low bone mineral density was increasingly prevalent among co-infected patients compared to HIV mono-infected controls (pooled OR 1.98, 95% CI 1.18, 3.31) but not those uninfected (pooled OR 1.47, 95% CI 0.78, 2.78). Significant association between co-infection and fracture was found compared to HIV mono-infected from cohort and case-control studies (pooled RR 1.57, 95% CI 1.33, 1.86) and compared to HIV/HCV uninfected from cohort (pooled RR 2.46, 95% CI 1.03, 3.88) and cross-sectional studies (pooled OR 2.30, 95% CI 2.09, 2.23).

Conclusions

The associations of co-infection with prevalent low BMD and risk of fracture are confirmed in this meta-analysis. Although the mechanisms of HIV/HCV co-infection’s effect on BMD and fracture are not well understood, there is evidence to suggest that adverse outcomes among HIV/HCV co-infected patients are substantial.     

藏红花提取液对去卵巢大鼠骨密度及骨代谢生化指标的影响

目的：研究中药藏红花提取液对去卵巢大鼠股骨骨密度及血清骨代谢生化指标的影响。方法：选用48只4月龄SD雌性大鼠,随机分为6组：假手术组、模型组、戊酸雌二醇组、藏红花低、中、高剂量组。术后4周各组分别给予相应制剂灌胃,术后12周处死,分别测定股骨骨密度、子宫指数、雌二醇、血钙、血磷、碱性磷酸酶。结果：与模型组相比,藏红花各剂量组股骨骨密度明显升高（p〈0.01）,雌二醇测定值升高（p〈0.01）,碱性磷酸酶显著降低（p〈0.01）,血钙及血磷无统计学差异（p〉0.05）;与戊酸雌二醇组比较,藏红花各剂量组子宫指数显著降低（p〈0.01）。结论：藏红花提取液有助于抑制去卵巢大鼠骨量的丢失,改善骨代谢,对骨质疏松症具有防治作用。