The effects of Choto-san on the mRNA expression of Alzheimer's disease related factors in the permanent ischemic rat brain

Choto-san is a Kampo medicines that has been used clinically for the treatment of dementia. We measured the mRNA expressions of some factors related to Alzheimer's disease in a dementia model rat brain. The expressions of beta-amyloid precursor protein, gamma-secretase, alpha7 nicotinic acetylcholine receptor, neprilysin, and insulin degrading enzyme (IDE) were significantly increased on day 4 after permanent occlusion of the bilateral common carotid arteries (2VO). Choto-san inhibited the enhancement of IDE expression caused by 2VO, although it failed to show any effects on the expressions of the other molecules. These results suggest that Choto-san may produce a state in which it is not necessary to induce IDE expression to demonstrate the anti-dementia effects.     

Wogonin inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion

The present study evaluated the effect of wogonin, a flavonoid originated from the root of Scutellaria baicalensis GEORGI, on focal ischemic brain injury in rats. Focal brain ischemia was induced by the permanent occlusion of middle cerebral artery (pMCAO) for 24 h with a silicone rubber cylinder inserted through the right internal carotid artery. We found that wogonin, intraperitoneally administered at a dosage of 20 mg/kg at 30 min before and 4 h after the surgery, reduced the pMCAO-induced infarct areas in the cerebral cortex as well as in the striatum. The total volume of infarction was significantly reduced by the treatment with wogonin. In addition, wogonin was found to significantly improve the pMCAO-induced behavioral deficits at 24 h after the surgery. Taken together, these results demonstrate that wogonin inhibits ischemic brain injury and improves behavioral dysfunction caused by pMCAO. These findings, along with previous reports demonstrating the neuroprotective effects of wogonin, provide strong pharmacological basis for the use of wogonin or Scutellaria baicalensis in the treatment of stroke.     

Valproate prevents MK801-induced changes in brain-derived neurotrophic factor mRNA in the rat brain

To investigate whether the anticonvulsant valproate influences the changes in brain-derived neurotrophic factor (BDNF) mRNA expression induced by MK801 in rat brain, we injected valproate prior to MK801 and observed the changes in the BDNF expression 3 h later. MK801 significantly increased BDNF expression in the retrosplenial and entorhinal cortex, and these increases were prevented by valproate pretreatment. Valproate pretreatment significantly blocked the MK801-induced increase of BDNF expression in retrosplenial cortex at 3 h, 6 h, and 9 h after MK801 injection, suggesting that valproate pretreatment did not delay the MK801-induced increase of BDNF expression. However, MK801 significantly decreased BDNF expression in the granule cell layer of hippocampus, and valproate pretreatment before MK801 potentiated the MK801-induced decrease in BDNF expression in granule cell layer. These results indicate that valproate pretreatment differentially affects the MK801-induced changes in BDNF expression in a region-selective manner.     

老年Ⅱ型糖尿病患者缺血性心脏病相关因素的分析

分析老年Ⅱ型糖尿病者缺血性心脏病的相关因素。方法 对９６例伴有和不伴有缺血性心脏的患者进行病程，糖指找谢，２４小时尿蛋白和空腹胰岛素分析。结果 前者平均水病病程，ＦＢＧ，ＰＢＧ，ＧＨＢ，ＦＩＮＳ，Ｔｃｈ和２４尿蛋白明显高于后者。     

缺血预处理对全脑缺血大鼠脑组织超微结构及细胞凋亡的影响

目的：为探讨脑缺血预处理对全脑缺血大鼠脑组织超微结构及细胞凋亡的影响。方法：本文以Wistar大鼠为受试对象,筛选后144只大鼠随机分为正常对照组(24只)、假手术组(24只)、脑缺血预处理对照组(32只)、脑缺血组(32只),脑缺血预处理组(32只)5组和术后12、24、48、72h四个时间点。采用“4-动脉阻断”方法建立大鼠全脑缺血模型,脑缺血后大脑皮层、海马CA1区HE染色观察组织形态学变化、电镜观察组织超微结构,原位末端标记(TUNEL染色)法检测神经元凋亡。结果：正常组、假手术组、脑缺血预处理对照组大脑皮层、海马CA1区无形态学改变,未见有细胞凋亡。脑缺血组大脑皮层、海马CA1区神经元缺失明显,12h、24h、48h、72h神经元凋亡逐渐加重。与脑缺血组相比,脑缺血预处理组大脑皮层、海马CA1区神经元损伤小,水肿程度轻,神经元形态恢复快,凋亡细胞数目少。结论：脑缺血预处理对全脑缺血大鼠大脑皮层、海马CA1区神经元具有保护作用,可以抑制全脑缺血大鼠大脑皮层、海马CA1区神经元凋亡。     

Selegiline treatment and the extent of degenerative changes in brain tissue of patients with Alzheimer's disease

BACKGROUND: A beneficial effect of selegiline (L-deprenyl) in Alzheimer's disease (AD) has been reported in several clinical studies. METHODS: The brain tissue from 17 deceased patients, members of a double-blind clinical trial to assess the potential benefit of selegiline in AD, were analysed. FINDINGS: In our study, the decrease in the Mini-Mental State Examination (MMSE) scores during the progress of the disease had been significantly influenced by selegiline treatment. Prior to death, the MMSE scores were significantly higher in those patients receiving selegiline than in those receiving placebo. However, according to our results, none of the lesions critical for AD diagnosis, such as counts of senile/neuritic plaques, neurofibrillary tangles or beta-A4 load, were influenced by the selegiline treatment. INTERPRETATION: In conclusion, according to our study, mechanisms other than neuronal degeneration seen as lesions critical for AD diagnosis are influenced by selegiline treatment, leading to the functional benefit found in AD.     

颈动脉硬化斑块及其相关因素与缺血性脑血管病的关系

目的 探讨颈动脉硬化（CAS）斑块及同型半胱氨酸（HCY）、C-反应蛋白（CRP）水平与缺血性脑血管病（ICVD）的关系。方法检测468例ICYD患者与456例非脑血管病患者（对照组）颈动脉内．中膜厚度（IMT）、斑块数及大小和性状,同时检测HCY和CRP水平并与对照组比较。结果（1）与对照组比较,ICVD组IMT明显增厚,CAS斑块检出率、软斑百分比明显增高（均P〈0．05）。（2）HCY和CRP水平ICVD组明显高于对照组（P〈0．05）;ICVD有斑块亚组明显高于无斑块亚组（P〈0．05）。（3）ICVD组颈动脉IMT与同型半胱氨酸和C反应蛋白水平呈正相关（r分别0．32、0．30,P〈0．05）。结论ICVD患者IMT增厚,CAS斑块及软斑发生率高,CAS斑块和高HCY血症是ICVD的独立危险因素,CRP水平是临床评价ICVD严重程度和预后的一个重要的指标。     

Chotosan enhances macrophage colony-stimulating factor mRNA expression in the ischemic rat brain and C6Bu-1 glioma cells

Macrophage colony stimulating factor (M-CSF) is a cytokine which has been recently reported to have a neuroprotective effect on ischemic rat brain. In this study, we investigated the effect of chotosan, an oriental medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on M-CSF gene expression in rats with permanent occlusion of bilateral common carotid arteries (P2VO) in vivo and in a C6Bu-1 glioma cell line in vitro. The expression level of M-CSF mRNA in the cerebral cortices of P2VO rats was significantly higher than that in the cerebral cortices of sham-operated animals. Repeated treatment of P2VO rats with chotosan (75 mg/kg per day) for 4 d after P2VO significantly increased the expression level of M-CSF mRNA in the cortex but it had no effect on the expression of beta-actin, granulocyte colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF) mRNAs. Moreover, the present in vitro studies revealed that chotosan treatment (10-100 mug/ml) of C6Bu-1 glioma cells dose-dependently enhanced M-CSF mRNA expression without affecting the expression of G-CSF, GM-CSF, and inducible nitric oxide synthase mRNAs. The effect of chotosan was reversed by Ro 31-8220 (1 muM), a selective protein kinase C (PKC) inhibitor, but not by H-89 (10 muM), a selective protein kinase A (PKA) inhibitor. These findings suggest that the upregulatory effect of chotosan on M-CSF mRNA expression involves PKC and may play an important role in the anti-vascular dementia action of this formula.     

Use of neuroimaging to detect early brain changes in people at genetic risk for Alzheimer's disease

The neuropathological and cognitive changes preceding Alzheimer's disease appear to begin subtly decades before symptoms of the disease make the clinical diagnosis obvious. Clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of Alzheimer's disease in people with only mild memory complaints. Because people with few cognitive deficits represent a heterogeneous population, prevention studies require large samples in order to detect active drug effects. To address such challenges, recent neuroimaging studies have focused on middle-aged and older adults with only mild memory complaints and evaluated results according to the major known genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele. In studies using positron emission tomography during mental rest and functional magnetic resonance imaging during memory task performance, brain patterns differ according to genetic risk and are useful in predicting future decline measures and following disease progression in clinical trials.     

Microglial dysfunction in brain aging and Alzheimer's disease

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial “activation” and “neuroinflammation” are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.     

Aluminium-induced changes in the rat brain serotonin system

Aluminium exposure, apart from producing cholinotoxicity, can include changes in other neurotransmitter levels since neurotransmitter levels are closely interrelated. Reports of aluminium (Al) effects on brain neurotransmitters are limited. To investigate the effect of Al on the rat brain serotonergic system, the present study was conducted to explore brain region-specific changes and duration-specific changes. Male Wistar albino rats were exposed orally to Al chloride (AlCl₃.6H₂O; 320 mg/kg body weight) daily for up to 60 days and changes in the 5-hydroxytrytamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) levels were observed after 4, 14 and 60 days of exposure in olfactory lobe (OLB), cerebellum (CBL), pons (PON), medulla oblongata (MOB), spinal cord (SPI), hypothalamus (HYP), hippocampus (HIP), striatum (STR), midbrain (MBR) and cortex (COR) brain regions. Significantly increased 5-HT levels observed in brain regions OLB (60 days), HIP (4,14 days), STR (14 days), HYP (14, 60 days), MBR (4 and 14 days), PON (4 days), MOB (4 days) and SPI (4, 14 and 60 days) following Al exposure may be due to Al deactivating 5-HT system by decreased release and subsequent breakdown of 5-HT. Decreased 5-HT levels observed in cerebral COR, HIP (60 days) and in CBL after 4 and 60 days of exposure suggest an inhibitory effect of Al on the 5-HT system due to withdrawal of cholinergic input in these brain regions. 5-HIAA level changes correlate with 5-HT level changes in many brain regions studied. The results reveal that the neurochemical changes due to Al were dependent on the duration of exposure and are brain-region-specific. The observed changes may be related to the cholinergic toxicity of Al.     

急性缺血性脑血管病患者脑动脉粥样硬化性狭窄的分布及相关因素分析

目的 探讨急性缺血性脑血管病患者脑动脉粥样硬化性狭窄的分布及其相关危险因素.方法 选取150例2005年1月至2009年1月期间于我院住院就诊的急性缺血性脑血管病患者为研究对象.所有患者行MRI和MRA检测、及血液生化指标检测,并通过问卷形式了解高血压病史、糖尿病史等因素.采用Logistic回归分析脑动脉狭窄的危险因素.结果 (1)动脉狭窄栓出率为74.00％.其中,单纯颅内动脉狭窄41.44％,单纯颅外动脉狭窄11.71％,颅外合并颅内动脉狭窄46.85％.轻度狭窄占26.13％,中度狭窄43.24％,重度狭窄30.63％.(2)高血压、糖尿病、冠心病、吸烟、LDL2C等为脑动脉狭窄的危险因素,HDL2C为保护因子.(3)根据MRI和MRA检查结果,将患者分为中度狭窄组、中度狭窄组和轻度狭窄组,随着狭窄程度逐渐变严重,CRP及IL-6有逐渐增加的趋势.结论 急性脑血管病患者中的动脉粥样硬化性狭窄发生率较高,可通过控制高血压、糖尿病、冠心病、吸烟等预防急性脑血管病.     

Distribution of 5-HT4 receptor mRNA in the rat brain

We have analyzed the brain distribution of the rat 5-HT₄ receptor mRNA. A receptor specific probe was used for in situ hybridization of rat brain sections. Abundant expression of the 5-HT₄ receptor mRNA was observed in the olfactory system, striatum, medial habenula and the hippocampal formation, while faint or no specific signals could be detected in most other areas of the brain. Several brain areas which display strong ligand binding do not contain mRNA, suggesting an axonal localization of the 5-HT₄ receptor.     

前阿黑皮原和强啡肽原基因在自发性高血压大鼠脑内的表达

目的：检测前阿黑皮原（ＰＯＭＣ）和强啡肽原（ＰＰＤ）基因在高血压（ＳＨＲ）和同龄Ｗｉｓｔａｒ－Ｋｙｏｔｏ大鼠（ＷＫＹ）中的表达。方法：用地高辛（ＤＩＧ）标记的ＲＮＡ探针进行原位杂交检测ＰＯＭＣ ｍＲＮＡ和ＰＰＤ ｍＲＮＡ。 结果：ＰＯＭＣｍＲＮＡ６主要表达于弓状核，而ＳＨＲ表达量大于ＷＫＹ。ＰＰＤ ｍＲＮＡ表达于海马、下丘脑、中脑中央灰质、孤束核、胸髓。在齿状回、孤束核、内侧视前区，ＳＨＲ ＰＯ     

Statin-like drugs for the treatment of brain cholesterol loss in Alzheimer's disease

Aging is one of the most significant risk factors for neurological disorders including Alzheimer's Disease (late-onset AD and sporadic AD), the most common form of dementia. AD is characterized by progressive atrophy and loss of neurons resulting in cognitive deficits, confusion and dementia, culminating in childlike helplessness and death. One of the major pathological hallmarks of the disease are amyloid plaques, composed primarly of insoluble fibrils of Abeta peptide: this molecule derives from the processing of the transmembrane amyloid precursor protein (APP) by different secretases and its production is a physiological event, but the anormal increase in Abeta levels appears to be toxic both in vitro and in vivo. Being APP cleavage a membrane event the involvement of lipids in alterations of this cleavage is assumable. Cholesterol is the most abundant lipid in cellular membranes and is an essential component of them, determining the fluidity and biophysical properties. In fact, genetic studies of the risk of AD have reported association with polymorphism in some cholesterol related genes like the allele epsilon4 of the apolipoprotein E, cholesterol 24-hydroxylase (CYP46A1), ATP-binding cassette transporter a1 (ABCA1) and the lipoprotein receptor-related protein (LRP). Moreover a recent publication shows a downregulation of Seladin-1 (which catalyze the last step of cholesterol biosynthesis) in affected neurons in Alzheimer's Disease. Post-mortem analysis of AD brains reveal a loss in cholesterol content and this make the therapeutical use of statin-like drugs quite a lot controversial. Taking together their clinical trials results and the large body of literature regarding lipid profile alterations in AD, it is actually unclear how much these agents can be helpful or not for affected patients.