缺氧缺血新生大鼠脑组织水通道蛋白4的表达变化

目的研究缺氧缺血性脑损伤(HIBD)病理过程中水通道蛋白4(aquaporin-4,AQP-4)的作用及其意义。方法120只7日龄新生Wistar大鼠按照完全随机化方法分为4部分,每部分(n=30)再分为对照组、HIBD后6h、24h、3d、5d和7d共6组,每组5只。分别测定脑组织含水量;原位杂交和免疫组化检测AQP-4表达;检测脑组织病理变化。结果HIBD组6h、24h、3d的脑组织含水量较对照组显著增加(P<0.05);且各组脑组织含水量随时间延长而增加,组间差异有统计学意义(P<0.05);HIBD5d、7d组脑组织含水量与对照组比较差异无统计学意义(P>0.05)。对照组AQP-4 mRNA和AQP-4蛋白少量表达(吸光度A值为0.29±0.07和0.06±0.01)。与对照组相比,HIBD后6~24h,AQP-4 mRNA和AQP-4蛋白表达显著增加。AQP-4 mRNA的A值由0.42±0.04上升到0.80±0.02(P<0.05);AQP-4蛋白A值由0.14±0.03上升到0.23±0.05(P<0.05),同时光镜下可见脑组织轻度水肿;3d时AQP-4 mRNA和蛋白表达达高峰,AQP-4 mRNA的A值为0.91±0.08,AQP-4蛋白A值为0.41±0.04,此时脑组织严重水肿,神经元、胶质细胞和内皮细胞明显肿胀;第5~7天AQP-4的表达已下降(尤其mRNA明显),但仍显著高于对照组(P<0.05),此时脑水肿已减轻。在整个HIBD脑水肿形成的过程中,AQP-4 mRNA和蛋白的表达呈正相关(rs>0.82,Ps<0.05)。结论AQP-4参与了HIBD的发生发展过程,AQP-4在HIBD脑水肿的形成过程中可能起重要作用。     

缺氧缺血新生大鼠脑组织水通道蛋白4的表达变化

目的 研究缺氧缺血性脑损伤(HIBD)病理过程中水通道蛋白4(aquaporin-4,AQP-4)的作用及其意义.方法 120只7日龄新生Wistar大鼠按照完全随机化方法分为4部分,每部分(n=30)再分为对照组、HIBD后6 h、24 h、3 d、5 d和7 d共6组,每组5只.分别测定脑组织含水量;原位杂交和免疫组化检测AQP-4表达;检测脑组织病理变化.结果 HIBD组6 h,24 h,3 d的脑组织含水量较对照组显著增加(P＜0.05);且各组脑组织含水量随时间延长而增加,组间差异有统计学意义(P＜0.05);HIBD 5 d,7 d组脑组织含水量与对照组比较差异无统计学意义(P＞0.05).对照组AQP-4 mRNA和AQP-4蛋白少量表达(吸光度A值为0.29±0.07和0.06±0.01).与对照组相比,HIBD后6～24 h,AQP-4 mRNA和AQP-4蛋白表达显著增加.AQP-4 mRNA的A值由0.42±0.04上升到0.80±0.02(P＜0.05);AQP-4蛋白A值由0.14±0.03上升到0.23±0.05(P＜0.05),同时光镜下可见脑组织轻度水肿;3 d时AQP-4 mRNA和蛋白表达达高峰,AQP-4 mRNA的A值为0.91±0.08,AQP-4蛋白A值为0.41±0.04,此时脑组织严重水肿,神经元、胶质细胞和内皮细胞明显肿胀;第5～7天AQP-4的表达已下降(尤其mRNA明显),但仍显著高于对照组(P＜0.05),此时脑水肿已减轻.在整个HIBD脑水肿形成的过程中,AQP-4 mRNA和蛋白的表达呈正相关(rs＞0.82,Ps＜0.05).结论 AQP-4参与了HIBD的发生发展过程,AQP-4在HIBD脑水肿的形成过程中可能起重要作用.     

脑出血大鼠大脑颞顶叶皮质水通道蛋白-4的表达

目的：研究脑出血脑水肿时，健侧大脑半球颞顶叶皮质水通道蛋白-4(AQP-4)表达变化及机制。 方法： 采用立体定向注射无肝素自体血制作大鼠脑出血模型,用MRI T2加权和病理学检查测定双侧半球颞顶叶皮质的水肿程度，RT-PCR和Western blotting检测两个部位AQP-4 mRNA和蛋白质的表达变化，最后从超微结构的角度探讨健侧半球颞顶叶皮质AQP-4改变的原因。 结果： 脑出血模型组大鼠出血侧和健侧颞顶叶皮质AQP-4表达均高于假手术组（P<0.05），脑出血1 d AQP-4 mRNA和蛋白即明显加强,第3 d达峰值,其后逐渐有所下降,但持续1周仍高于假手术组。健侧AQP-4表达弱于出血侧，但仍高于假手术组。电镜观察结果：出血侧颞顶叶皮质出现神经元水样变性，健侧颞顶叶皮质神经细胞核膜间隙无扩张，核周体无明显空泡形成，但线粒体明显肿胀呈球形,部分嵴断裂或溶解消失,透明成空泡;粗面内质网扩张,表面核糖体出现脱落，提示该部位细胞水肿不明显，但是出现了缺氧性改变。 结论： 脑出血后健侧颞顶叶皮质AQP-4在水肿不明显的情况下出现表达增强，其增高可能与脑缺氧有关。     

Dexamethasone treatment modulates aquaporin-4 expression after intracerebral hemorrhage in rats

This study investigated whether dexamethasone (DEX) treatment could regulate the expression of aquaporin-4 (AQP4) in rats with intracerebral hemorrhage (ICH). The results demonstrated that DEX significantly reduced AQP4 mRNA level in the perihematomal area compared with control group, but it increased the level in the brain area surrounding the third ventricle at day 1 post-ICH. There was no difference in AQP4 protein levels between DEX group and control group at the two above-mentioned brain regions at day 1 after ICH. The changes in AQP4 protein induced by DEX were marked at day 3 following surgery and still lasted at day 5 post-ICH, which were accompanied by a reduction of brain edema. Our results demonstrated that the expression of AQP4 protein after ICH was region-specific, time-dependent, and also indicated that DEX-induced cerebral edema clearance was correlated with the regulation of AQP4 expression in different brain regions.     

Muscarinic agonist receptor subtypes in aging rat brain

Whole brain homogenates from rats aged 6 months (young) and 24 months (old) showed a decline with age of the pre-synaptic cholinergic marker, choline acetyltransferase, and also of total specific binding sites for the muscarinic antagonist L(?)quinuclidinyl benzilate (L-QNB). However, neither the proportion nor the inhibition constants of high and low affinity muscarinic agonist binding sites (defined by displacement of L-QNB binding with carbachol) changed with age. These findings may be relevant to the central cholinergic deficit reported to be associated with cognitive impairment in aging man.     

Intracerebroventricular administration of an endothelin ETB receptor agonist increases expression of tissue inhibitor of matrix metalloproteinase-1 and -3 in rat brain

Production of tissue inhibitors of matrix metalloproteinases (TIMPs), a family of secreted proteins with inhibitory actions on matrix metalloproteinases (MMPs), is up-regulated following nerve injuries and is suggested to have protective effects against MMP-mediated tissue damages. To clarify the extracellular signals involved in TIMP production in the brain, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/day Ala(1,3,11,15)-ET-1, an ET(B) receptor agonist, increased the level of TIMP-1 mRNA in rat hippocampus, caudate-putamen and cerebrum. Ala(1,3,11,15)-ET-1 increased the level of TIMP-3 mRNA in the cerebrum, but not in the hippocampus or caudate-putamen. TIMP-2 mRNA was not affected in these brain regions. Ala(1,3,11,15)-ET-1 also stimulated the production of TIMP-1 and TIMP-3 proteins in the cerebrum. Immunohistochemical observations in the hippocampi of Ala(1,3,11,15)-ET-1-infused rats showed that NeuN-positive neurons and glial fibrillary acidic protein-positive astrocytes were immunoreactive for TIMP-1. In the cerebrum, astrocytes had TIMP-1 and TIMP3 reactivity, but neurons did not. In rat cultured astrocytes, both 100 nM Ala(1,3,11,15)-ET-1 and ET-1 increased the mRNA levels and protein release of TIMP-1 and TIMP-3 mRNAs. The effects of ET-1 on astrocytic TIMP-1 and TIMP-3 mRNAs were inhibited by BQ788, an ET(B) antagonist. These findings indicate that activation of brain ET(B) receptors causes production of TIMP-1 and TIMP-3, and suggest the involvement of astrocytes in ET-induced TIMP production.     

Role of ETA and ETB endothelin receptors on endothelin-1-induced potentiation of nociceptive and thermal hyperalgesic responses evoked by capsaicin in rats

Increasing evidence indicates that endothelin-1 (ET-1) activates nociceptive neurons and sensitizes them to different noxious stimuli, but involvement of TRPV1-dependent mechanisms in mediation of such effects is not yet fully understood. Here we report that intraplantar (i.pl.) injection of ET-1 (10 pmol) into the hind paw of rats induced overt nociceptive behavior over the first hour, followed by a slowly developing thermal hyperalgesia, lasting from 3 to 8 h after injection. Both effects were also induced by similar injections of capsaicin (10–1000 pmol), but these responses were shorter lasting than those caused by ET-1. Local pre-treatment with the TRPV1 antagonist capsazepine (30 nmol, i.pl.) reduced only the thermal hyperalgesia induced by ET-1, but fully suppressed both responses to capsaicin (1000 pmol). Injection of a sub-threshold dose of ET-1 (0.1 pmol, i.pl.) prior to capsaicin (1 pmol, i.pl.) markedly sensitized the hind paw to the overt nociceptive and thermal hyperalgesic effects of the later. The potentiation of capsaicin-induced nociception by ET-1 was abolished by prior i.pl. injection of BQ-123 (ET_A receptor antagonist, 10 nmol), but unaffected by BQ-788 (ET_B receptors antagonist, 10 nmol), whereas the enhancement of capsaicin-induced hyperalgesia by ET-1 was attenuated by both antagonists. Therefore, differently to what has been reported in mice, in rats TRPV1 receptors contribute selectively to thermal hyperalgesia, but not overt nociception, induced by ET-1. Importantly, although ET-1 augments capsaicin-induced overt nociception and thermal hyperalgesia, potentiation of the former relies solely on ET_A receptor-mediated signaling mechanisms, whereas both receptors contribute to the latter.     

地塞米松对大鼠胸膜间皮细胞水通道蛋白1表达的调节

 目的：观察胸膜间皮细胞水通道蛋白1（AQP-1）的表达及地塞米松（Dex）对其表达的影响，为进一步研究胸水治疗的机制提供实验依据。方法:体外培养大鼠胸膜间皮细胞，细胞鉴定后，采用免疫细胞化学、RT-PCR方法检测AQP-1表达；应用Western blotting检测以不同浓度Dex（10^-8、10^-7、10^-6、10^-5、10^-4 mmol/L）处理细胞 24 h 及以10^-4 mmol/L Dex处理细胞 6 h、12 h、24 h、36 h、48 h、72 h后AQP-1表达情况。结果:发现胸膜间皮细胞存在AQP-1表达， 10^-8、10^-7、10^-6、10^-5、10^-4 mmol/ L Dex干预胸膜间皮细胞 24 h 后，AQP-1蛋白表达量(积分吸光度)分别为755.04±19.81、843.72±19.41、862.96±26.53、694.80±32.00、938.08±13.32，分别高于正常对照组（372.90±16.46） 2.02、2.26、2.31、1.86、2.52倍 (P<0.01)，AQP-1表达升高与地塞米松浓度无关；以10-4 mmol/L Dex干预细胞 6 h、12 h、24 h、36 h、48 h、72 h 后，AQP-1蛋白表达量分别为：554.14±23.57、917.78±38.62、1 587.20±61.22、1 322.09±28.65、918.40±26.62、1 117.60±51.32，分别高于正常对照组（495.91±23.12）1.12、1.85、3.20、2.67、1.85、2.25倍(P<0.01)，AQP-1表达与地塞米松作用时间有关。结论:胸膜间皮细胞存在AQP-1表达，地塞米松对胸膜间皮细胞AQP-1表达有明显的增强性调节作用，具有时间依赖性。     

内皮素及其受体拮抗剂对新生大鼠心室肌细胞起搏电流及其基因表达的影响

目的： 运用膜片钳全细胞技术和实时定量聚合酶链式反应（PCR），研究内皮素-1（ET-1）及其受体拮抗剂对新生大鼠心室肌起搏电流（If）及其基因表达的影响。方法：分离1-3 d新生大鼠的心室肌细胞；测定超极化激活的环核苷酸门控通道（HCN）亚型1、HCN2、HCN3和HCN4的表达情况；记录If并研究其特性。其次分别用不同浓度(0、1、10、100 nmol/L) ET-1刺激细胞3 h，用100 nmol/L ET-1刺激细胞不同时间（0、0.5、1、3、6 h），用100 nmol/L ET-1加1 000 nmol/L ETA拮抗剂（BE-18257B）或ETB拮抗剂（IRL-1038）刺激心肌细胞3 h，观察ET-1对If和HCN的影响。 结果：HCN1、HCN2、HCN3和HCN4在总HCN的表达中所占比例分别为(0.23±0.01)%、(83.58±0.04)%、(0.79±0.01)%、(15.44±0.01)%。全细胞膜片钳记录到超极化激活、4 mmol/L CsCl可阻断If；10、100 nmol/L ET-1刺激3 h后，HCN2分别增加0.1、2倍，HCN4增加0.1、0.5倍；相同浓度ET-1刺激不同时间后，HCN2增加0.3、1、5、5.1倍，HCN4增加0.1、0.6、2、2.1倍，而ET-1对HCN1和HCN3无显著影响；加BE-18257B后HCN2和HCN4表达明显降低，If减小；而IRL-1038对HCN表达和If无显著影响。结论：（1）新生大鼠心室肌HCN的表达以HCN2和HCN4为主，并有超极化激活的If；（2）ET-1使其HCN2和HCN4表达增加，If增大，其作用主要通过ETA受体实现。     

Induction of P-glycoprotein expression in astrocytes following intracerebroventricular kainate injections

 The expression of P-glycoprotein (PGP) was studied by immunocytochemistry and light and electron microscopy, in normal rats and after intracerebroventricular kainate injections. Two antibodies to PGP, mdr (Ab-1) and c-219, were used. As in previous studies (Thiebault et al. and Jetté et al.), labelled capillaries were observed in normal rats. Kainate injections resulted in death of pyramidal neurons in the hippocampus, and a proliferation of glial cells in the affected cornu ammonis fields. An increase in PGP expression was observed in reactive astrocytes as early as 1 day postinjection. Immunoreactivity peaked at 2 weeks postinjection, but was still visible as late as 10 weeks postinjection. Similar results were observed using the two antibodies. Double immunolabelling and confocal microscopy also showed that PGP was colocalised with GFAP, a marker for astrocytes. The expression of PGP in astrocytes was confirmed by electron microscopy, which showed immunoreaction product in cells containing dense bundles of glial filaments and features of reactive astrocytes. The increased PGP expression in reactive astrocytes could be part of a cellular stress response program in these cells. Received: 17 August 1998 / Accepted: 26 January 1999     

Expression of endothelin system in neuroblastic tumors: close association of endothelin-1 and endothelin B receptor expression with differentiation of tumor cells

Although a critical role of the endothelin (ET) system in differentiation of neural crest cells has been reported, implication of the ET system in human neuroblastic tumors has not been fully elucidated. We immunohistochemically examined for localization of ET-1, ET-3, ET-A receptor (ET-A), and ET-B receptor (ET-B) in 24 ganglioneuromas, 8 ganglioneuroblastomas, 37 neuroblastomas, 14 normal sympathetic ganglia, and 10 fetal adrenal glands with regard to neuroblastic cell differentiation. Neuroblasts in fetal adrenal glands expressed ET-B (100%) alone. Immature ganglionic cells in sympathetic ganglia of fetus frequently expressed ET-1 (86%) and ET-B (100%), while ET-A was occasionally detected (28%). Ganglionic cells of mature adult ganglia consistently harbored ET-1 (100%) and, infrequently, ET-3 (21%) or ET-B (29%). Expression of ET-1 and ET-B was closely associated with tumor cell differentiation: the expression frequency of ET-1 or ET-B was 16% or 46% in neuroblastomas; 100% or 88% in ganglioneuroblastomas; and 96% or 92% in ganglioneuromas. In contrast, ET-3 and ET-A showed no association with tumor cell differentiation: the expression frequency of ET-3 or ET-A was 26% or 14% in neuroblastomas; 63% or 13% in ganglioneuroblastomas; and 29% or 21% in ganglioneuromas. In conclusion, ET-1 and ET-B are expressed with differentiation of neuroblastic tumors.     

大鼠皮质N-甲基-D-天冬氨酸受体在脑损伤后的时相变化

目的；观测Ｎ－甲基－Ｄ－天冬氨酸（ＮＭＤＡ）受体在脑损伤后的变化规律以及与继发性脑水肿发生和发展的关系。方法：用放射性配基结合分析法对伤后不同时间的大鼠伤侧大脑皮质ＮＭＤＡ受体活性进行测定干湿法测伤后伤测皮质水含量。     

LPS对鼠肺微血管内皮细胞水通道蛋白-1表达及其功能的影响

目的：通过观察脂多糖（LPS）刺激对肺微血管内皮细胞水通道蛋白-1 mRNA表达和功能的影响，以探讨急性肺损伤肺水异常代谢的机制。方法： 在体外培养的大鼠肺微血管内皮细胞（RLMEC），分别使用浓度为100 μg/L、1 mg/L、10 mg/L的LPS与之孵育4 h、12 h、24 h后, 应用氚水掺入法测定RLMEC内氚水的信号强度，并用RT-PCR法测定AQP-1 mRNA的表达。结果： LPS刺激组氚水的信号强度显著低于对照组（P<0.01）；同时LPS刺激组AQP-1 mRNA的表达显著低于对照组。结论： LPS刺激RLMEC AQP-1 mRNA表达和摄水功能下降，提示AQP-1在急性肺损伤时可能与肺水代谢异常有关。     

水通道蛋白5在大鼠大脑组织中的分布及表达

目的:观察水通道蛋白5(AQP5)在大鼠脑组织中的分布和表达,为研究脑组织中水分子的运输和平衡机制提供形态学基础。方法:运用免疫组织化学和免疫荧光技术,观察正常成年Wistar大鼠脑组织中AQP5的分布;运用免疫印迹观察AQP5的表达,并与AQP4在脑组织的分布和表达进行比较。结果:AQP5分布于大脑皮质的软脑膜、脉络丛、血管周围、海马锥体细胞层、齿状回颗粒细胞层、视上核、视交叉上核内和大脑纵裂两侧皮质深部,与AQP4分布范围相似;除此以外,AQP5还独自分布于大脑皮质下神经细胞。免疫印迹显示AQP5表达明显弱于AQP4。结论:AQP5在大鼠脑组织中分布广泛,可能协同AQP4在脑组织水运输平衡,脑脊液产生与回流及渗透压的调节过程中,发挥重要作用。     

Blood brain barrier (BBB) dysfunction associated with increased expression of tissue and urokinase plasminogen activators following peripheral thermal injury

Emerging data suggests the serine proteases, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA), may play a detrimental role in traumatic states leading to compromise of the blood brain barrier (BBB). The purpose of our study was to define the role of endogenous tPA and uPA on the BBB following peripheral burn injuries. Adult male Sprague–Dawley rats (n = 46) were studied in control and thermal injury groups. Rats were anesthetized and submerged in 100 °C water for 6 s producing a third degree burn affecting 60–70% of the total body surface area. BBB dysfunction was then evaluated by measuring the amount of Evans blue and by calculating the water content in the brain. Levels of tPA and uPA mRNA in the brain were determined with real-time polymerase chain reaction (PCR) at 3 and 7 h post-injury. Results showed an increase in the brain water content and the presence of Evans blue in the brain tissue of thermally injured rats, temporally associated with an increased expression of endogenous tPA and uPA. Our study demonstrates that peripheral thermal injury does induce an increase in the permeability of the BBB. A possible mechanism may be an increased expression of tPA and uPA.     

Role of aminoguanidine in brain protection in surgical brain injury in rat

The study investigated the effect of aminoguanidine (AG) on surgical brain injury (SBI) in rat. AG (75, 150 and 300 mg/kg, i.p.) was administered immediately following surgical resection. Using a SBI model, we found that AG (150 mg/kg) significantly reduced cerebral edema, while AG at the doses of 75 and 300 mg/kg had no effect. And AG (150 mg/kg) significantly reduced Evans Blue extravasation into brain tissue and improved the neurological outcome compared to control group. Moreover, the expression of TNF-alpha and nuclear factor-kappaB (NF-kappaB) mRNA and protein in brain tissue at the edge of the resection site increased at 24h after SBI, which could be significantly attenuated by the treatment with AG via RT-PCR and Western blots methods. Our results demonstrated that SBI causes increased brain edema, BBB disruption and inflammation along the periphery of the site of surgical resection, which could be significantly improved by the treatment of AG.     

Coronary arteriopathy in monkeys following administration of CI-1020, an endothelin A receptor antagonist

A selective non-peptide endothelin A (ETA) receptor antagonist, CI-1020, was administered to cynomolgus monkeys intravenously (i.v.) for 2 or 4 wk and orally for 4 wk. Groups consisting of 3 animals of each sex received CI-1020 at 1, 5, and 10 mg/kg/hr (i.v.) or orally at 250, 500, and 750 mg/kg body weight for 4 wk. Control animals received the vehicle only. In a separate experiment, 1 male was infused with 10 mg/kg/hr for 2 wk, and Monastral blue dye was administered i.v. to facilitate localization of lesions to the vascular walls. One female was administered saline and the dye and served as a control. One female at 1 mg/kg/hr was found dead at week 2, and 1 female at 5 mg/kg/hr was euthanatized during week 4 as a result of severe thigh swelling at the catheter site. Macroscopically, extramural coronary arteries appeared thickened and nodular in the 4-wk i.v. study in the female found dead at 1 mg/kg/hr, in 1 male and 1 female at 5 mg/kg/hr, and in 2 females at 10 mg/kg/hr. Histologically, Monastral blue pigment trapped in the walls of coronary arteries with arteriopathy was observed in the male treated with CI-1020 at 10 mg/kg/hr for 2 wk. Extramural coronary arteriopathy occurred at all doses in the 4-wk i.v. study, with higher incidence occurring in females than in males (7 of 9 treated females compared with 3 of 9 treated males). In the oral study, 1 female at 500 mg/kg/day and 1 male and 2 females at 750 mg/kg/day had coronary arteriopathy. Histological changes after 2 wk of treatment were characterized by intimal thickening, fragmentation of the internal elastic lamina, necrosis and edema of the media, and mixed inflammatory-cell infiltrates in the intima, media, and adventitia. After 4 wk of i.v. administration, arteriopathy was characterized by segmental disruption of the elastic lamina and intimal and medial fibrosis with complete replacement of smooth muscle with fibrous tissue. The adventitia was thickened as a result of fibrosis and mixed or mononuclear inflammatory-cell infiltrates. CI-1020 concentrations were higher in males (1.57 to 29 micrograms/ml) than in females (0.974 to 24.4 micrograms/ml) in the i.v. study. Transient systemic exposure with high maximum plasma concentration (Cmax) (120-352 micrograms/ml) in the oral study was insufficient to provoke arterial changes of the same magnitude as those noted with continuous i.v. administration. The regeneration of the media by fibrous tissue and the disruption of the elastic lamina may weaken the arterial wall and increase the susceptibility of the artery to the development of aneurysm.     

Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis

Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1×10⁷ cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX + DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX + DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX + DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem.     

CART肽抑制缺血再灌注小鼠脑组织水通道蛋白4表达并减轻脑水肿

目的:研究可卡因及苯丙胺调节转录物(CART)肽对小鼠脑缺血再灌注急性期脑水肿的作用,并探讨其作用机制。方法:清洁级雄性ICR小鼠随机分为假手术(sham)组、大脑中动脉栓塞(MCAO)组和CART组,复制小鼠MCAO模型以模拟局灶性脑缺血再灌注损伤病理过程,TTC染色法计算脑梗死体积及脑水肿体积,干湿重法测定脑组织中水含量,通过检测伊文思蓝含量判断血脑屏障(BBB)的完整程度,免疫荧光和Western blot观察脑组织水通道蛋白4(AQP-4)的表达变化。结果:小鼠MCAO后24 h,CART肽处理组小鼠脑梗死体积和脑水肿体积均明显小于MCAO组(P0.01),脑组织水含量亦明显低于MCAO组(P0.01)。伊文思蓝测定表明,CART肽能够有效维持血脑屏障的完整性。免疫荧光和Western blot结果显示,MCAO小鼠脑组织中AQP-4表达明显升高,而CART处理明显抑制脑缺血再灌注诱导的AQP-4表达(P0.05)。结论:CART肽可减轻脑缺血再灌注损伤小鼠急性期脑水肿,维持血脑屏障完整性,其作用机制可能与抑制脑组织AQP-4表达水平密切相关。     

LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor

We have determined the pharmacological profile of the new serotonin 5-HT₇ receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT₇ receptor (5-HT₇^−/−) and their 5-HT₇^+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT₇ receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT₇^+/+ but not in 5-HT₇^−/− mice. Our results suggest that LP-211 can be used as a 5-HT₇ receptor agonist in vivo.