Development of cerebral infarction, apoptotic cell death and expression of X-chromosome-linked inhibitor of apoptosis protein following focal cerebral ischemia in rats

The aim of this study was to investigate the role of apoptosis or necrosis in the development of delayed infarct, and the relationship between the level of XIAP gene, caspase-3 activation and ischemic cell death following transient focal cerebral ischemia. Adult male Sprague-Dawley rats underwent right middle cerebral artery occlusion (MCAo) for 50 min and reperfusion for 0.5, 4, 8, 24 h, 3, 7, 14 days. On TTC-stained coronal sections, delayed infarct was observed to develop in the whole MCA territory, especially in frontoparietal cortex after ischemia. Near total infarct was shown in striatum 24 h after MCAo, while delayed infarct was evident in the cortex. By day 3, the infarct had progressively expanded to the nearly whole area of the frontoparietal cortex. Flow cytometric analysis of Annexin-V (marks apoptosis) and PI (propidium iodide, marks necrosis) labeling cells showed that MCAo dominantly induced necrosis in ischemic core, striatum. Apoptosis contributed to delayed infarct and cell death in the border zone, dorsolateral cortex and hippocampus. The time-course of caspase-3 activation was consistent with the changes of apoptosis and infarct following MCAo. Further RT-PCR experiments indicated that there was a biphasic regulation of XIAP in time- and region-dependent manner after ischemia. In the infarct core (striatum), following a transient and slight increase during 0.5 h to 4 h post-MCAo, expression of XIAP mRNA markedly decreased. On the other hand, a longer and larger upregulation of XIAP was observed at early time points in border zone (0.5 to 8 h, in dorsolateral cortex; 0.5 to 24 h in hippocampus), then the level of XIAP reduced. A negative correlation was observed between apoptosis and regulation of XIAP gene in these regions. Our findings suggest a possible association between expression of XIAP gene, apoptosis and delayed infarct following ischemia.     

Urotensin-II is a nitric oxide-dependent vasodilator in the pial arteries of the newborn pig

Urotensin-II (UT-II) is a small circular peptide and is described as the most potent endogenous vasoconstrictor in various vascular beds. However, the in vivo effects of UT-II can be either vasoconstriction or vasodilation depending on the species and the tissue investigated. The present study sought to characterize the vasoactive effect of UT-II in the piglet cerebral circulation in vivo. Pial arteries of 99 +/- 6 microm were visualized with intravital microscopy through a closed cranial window in anesthetized newborn piglets. Topical application of UT-II elicited a weak dose-dependent vasodilation of the arteries (0.001 microM: 3 +/- 3 microm, 0.1 microM: 10 +/- 5 microm, 10 microM: 14 +/- 7 microm). Smaller arteries with an initial diameter below 100 microm showed minimal or no vasodilation, while larger arteries between 100 and 120 microm had a pronounced dose-dependent effect. Systemic application of 15 mg/kg Nomega-nitro-L-arginine-methyl ester (L-NAME) completely inhibited the vasodilation. We conclude that UT-II, in contrast to most other vascular beds, is a weak NO-dependent vasodilator in the piglet pial vasculature.     

A model of the interaction between autoregulation and neural activation in the brain

In this paper a model is proposed that predicts the response of the cerebral vasculature to changes in arterial blood pressure, arterial CO2 concentration and neural stimulation. Cerebral blood flow (CBF) is assumed to be controlled through changes in arterial compliance, and hence arterial resistance and volume, through three feedback mechanisms, which act in a linear additive manner, based on CBF, arterial CO2 and neural stimulus. Together with arterial, capillary and venous compartments, a tissue compartment is included, which contributes partly to the initial rise found in the deoxyhaemoglobin response to neural activation. Dynamic simulations of the model under different conditions show that there is significant interaction between the autoregulation and activation processes, and that the level of autoregulation has a strong influence on the CBF and deoxyhaemoglobin responses to neural activation. Overshoot in the deoxyhaemoglobin response is eliminated completely in the absence of this regulation. The feedback mechanism time constants significantly affect the CBF and deoxyhaemoglobin responses. Changes in arterial blood pressure (ABP) are found to have a strong influence on the neural activation response, with the amplitude of the response decreasing significantly at high baseline ABP. Dynamic changes in ABP also have a significant and potentially confounding impact on the measured deoxyhaemoglobin response to neural activation.     

脑动静脉畸形的MRA诊断技术及诊断价值

目的：回顾性分析脑动静脉畸形（AVM）的MRA诊断方法厦诊断价值。方法：51例AVM病人,男30人,女21人,年龄为9—66岁。均进行MR平扫压3D—TOFMBA或3D—PCMBA扫描。结果：删能清晰显示瘤巢压AVM的继发改变,MBA可基本显示AVM的全貌。结论：船认是诊断AVM的有效方法,但常需结合DSA。     

脑卒中偏瘫患者临床康复的护理效应

目的：通过脑卒中偏瘫患者4期的康复护理训练的疗效观察,探讨康复训练护理对脑卒中偏瘫患者的功能恢复的临床效果。方法：本贵料收集2004年1月至2004年12月共75例脑卒中偏瘫患者,随机分为两组,对照组和康复组,均采用内科常规护理,康复组接受康复护理训练;而对照组不进行康复护理训练。采用Banher指数评分法予以评定。结果：康复组功能改善程度明显高于对照姐（P〈0．05）。结论：脑卒中偏瘫患者日常生活活动能力改善在很大程度上取决于早期运动功能的恢复。对脑卒中偏瘫的早期功能恢复是必要的、有益的。     

Age-Related Changes of GABA-Activated Chloride Channel Properties in Brain Cortex Synaptic Plasma Membrane: Evidence for Phospholipase Involvement

Abstract: Brain aging decreases binding of tert -butylbicyclophosphorothionate (TBPS), a specific ligand for Cl⁻ channels, but has no effect on Cl⁻ influx. Detailed studies on the kinetics of TBPS dissociation allowed the characterization of Cl⁻ channel properties. Aging lowers, exclusively in the presence of GABA agonist, muscimol, the half-life of the fast phase of TBPS dissociation, indicating an opening time of receptor-dependent Cl⁻ channels shorter than that in adult brain. The half-life of the slow phase of TBPS dissociation is significantly lower in aged brain in the presence and absence of muscimol. These results suggest a sustained Cl⁻ current, including also the other channel(s) not connected with GABA_A receptor activation. The analysis of biphasic TBPS dissociation demonstrates a lowered number of binding sites resulted in the reduction of the number of Cl⁻ channels in the "open" state. This may explain an observed decrease of TBPS binding in aged brain. One of the possible factors involved in modification of GABA_A receptor behavior during aging may be arachidonic acid or diacylglycerol, known to be accumulated in aged brain. The action of these compounds on the Cl⁻ channel, observed in this study, correlates well with the effect of aging.     

NOX2 deficiency ameliorates cerebral injury through reduction of complexin II-mediated glutamate excitotoxicity in experimental stroke

Although NADPH oxidase (NOX)-mediated oxidative stress is considered one of the major mechanisms triggering the pathogenic actions of ischemic stroke and very recent studies have indicated that NADPH oxidase is a major source of reactive oxygen species (ROS) production controlling glutamate release, how neuronal NADPH oxidase activation is coupled to glutamate release is not well understood. Therefore, in this study, we used an in vivo transient middle cerebral artery occlusion model and in vitro primary cell cultures to test whether complexins, the regulators of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes necessary for vesicle fusion, are associated with NOX2-derived ROS and contribute to glutamate-mediated excitotoxicity in ischemic stroke. In this study, we first identified the upregulation of complexin II in the ischemic brain and evaluated its potential role in ischemic stroke showing that gene silencing of complexin II ameliorated cerebral injury as evidenced by reduced infarction volume, neurological deficit, and neuron necrosis accompanied by decreased glutamate levels, consistent with the results from NOX2^−/− mice with ischemic stroke. We further demonstrated that complexin II expression was mediated by NOX2 in primary cultured neurons subjected to oxygen–glucose deprivation (OGD) and contributed to OGD-induced glutamate release and neuron necrosis via SNARE signaling. Taken together, these findings for the first time provide evidence that complexin II is a central target molecule that links NADPH oxidase-derived ROS to glutamate-mediated neuronal excitotoxicity in ischemic stroke.     

Crystal Structure of CCM3, a Cerebral Cavernous Malformation Protein Critical for Vascular Integrity

CCM3 mutations are associated with cerebral cavernous malformation (CCM), a disease affecting 0.1–0.5% of the human population. CCM3 (PDCD10, TFAR15) is thought to form a CCM complex with CCM1 and CCM2; however, the molecular basis for these interactions is not known. We have determined the 2.5 Å crystal structure of CCM3. This structure shows an all α-helical protein containing two domains, an N-terminal dimerization domain with a fold not previously observed, and a C-terminal focal adhesion targeting (FAT)-homology domain. We show that CCM3 binds CCM2 via this FAT-homology domain and that mutation of a highly conserved FAK-like hydrophobic pocket (HP1) abrogates CCM3-CCM2 interaction. This CCM3 FAT-homology domain also interacts with paxillin LD motifs using the same surface, and partial CCM3 co-localization with paxillin in cells is lost on HP1 mutation. Disease-related CCM3 truncations affect the FAT-homology domain suggesting a role for the FAT-homology domain in the etiology of CCM.     

Overexpression of Human Apolipoprotein A-I Preserves Cognitive Function and Attenuates Neuroinflammation and Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer Disease

To date there is no effective therapy for Alzheimer disease (AD). High levels of circulating high density lipoprotein (HDL) and its main protein, apolipoprotein A-I (apoA-I), reduce the risk of cardiovascular disease. Clinical studies show that plasma HDL cholesterol and apoA-I levels are low in patients with AD. To investigate if increasing plasma apoA-I/HDL levels ameliorates AD-like memory deficits and amyloid-β (Aβ) deposition, we generated a line of triple transgenic (Tg) mice overexpressing mutant forms of amyloid-β precursor protein (APP) and presenilin 1 (PS1) as well as human apoA-I (AI). Here we show that APP/PS1/AI triple Tg mice have a 2-fold increase of plasma HDL cholesterol levels. When tested in the Morris water maze for spatial orientation abilities, whereas APP/PS1 mice develop age-related learning and memory deficits, APP/PS1/AI mice continue to perform normally during aging. Interestingly, no significant differences were found in the total level and deposition of Aβ in the brains of APP/PS1 and APP/PS1/AI mice, but cerebral amyloid angiopathy was reduced in APP/PS1/AI mice. Also, consistent with the anti-inflammatory properties of apoA-I/HDL, glial activation was reduced in the brain of APP/PS1/AI mice. In addition, Aβ-induced production of proinflammatory chemokines/cytokines was decreased in mouse organotypic hippocampal slice cultures expressing human apoA-I. Therefore, we conclude that overexpression of human apoA-I in the circulation prevents learning and memory deficits in APP/PS1 mice, partly by attenuating neuroinflammation and cerebral amyloid angiopathy. These findings suggest that elevating plasma apoA-I/HDL levels may be an effective approach to preserve cognitive function in patients with AD.