Molecular mechanisms of neurodegeneration and encephalopathy in the rat brain with chronic cerebral hypoperfusion

慢性脑低灌注大鼠脑神经变性和脑病的分子机制

• 批准号: 13470512
• 负责人: WATANABE Hiroshi
• 金额: $ 7.23万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470512/
• 关键词: learning and memory; bilateral common carotide arteries; differential display; cloning; oxindole alkaloids; pH-sensitive liposome; antisense; Xenopus oocyte; 痴呆; 遺伝子発現; RT; PCR; 釣藤散; ツメガエル卵母細胞; セロトニン; 興奮性アミノ酸; 遺伝子発現変化; 水迷路; 青班核; ノルァドレナリ

The rat with chronic cerebral hypoperfusion which is produced by permanent occlusion of bilateral common carotide arteries (2VO) is a useful model to study for dementia. The 2VO rat exhibited impairment of learning and memory behavior and histological rarefaction in the white matter of the brain. To isolate the intrinsic factors in the brain which induce dementia and rarefaction, the differential display method (DD) was applied to mRNAs isolated from 2VO- and sham-operated rat brains for 4 days. One of the factors which dramatically changed the expression was detected and it named vof-21. Although the clarified sequence by DD was only 415 nt, the whole sequence of vof-21, 4,885 nt, was also recloned. Vof-21 sequence was a novel and the sequence was submitted to gene bank, No. AB089205. The expression was shown a peak at 7 days after 2VO, and then decreased to the sham level at 35 days. The expression was abundant in the brain and the lung followed by in the thymus. The results of in si … More tu hybridization revealed that the expressions in brain were rich in locus coreuleus, pontine nucleus and hippocampus. The RT/PCR shows that vof-21 mRNA also existed in NG108-15 cells. To inhibit the expression in this cells, the conditions of pH-sensitive liposome methods were established and reported. The functional significance of vof-21 was still studying by using of this liposome system especially on Ca2+ and other ion channel and/or mobility. Several studies demonstrated that some of the oxindole alkaloids of Uncaria species have the memory improving and neuroprotective effect in the animal models. Therefore, the effects of Uncaria alkaloids on the neurotransmitter receptor functions were studied by using the electrophysiolgical system to clarify the possible mechanisms underlying the neuropharmacological actions. The results show that pentacyclic oxindole alkaloids (pteropodine and isopteropodine)enhanced the electrophysiological response induced by M1 and 5-HT2 receptor activation in Xenopus oocyte injected brain RNA. On the other hand, tetracyclic oxindole alkaloids (rhynchophylline and isorhynchophylline) inhibited NMDA response. It has been well known that muscarinic receptor inhibition and NMDA receptor stimulation induced dementia and neuronal cell death, respectively. Thus these mechanisms of oxindole alkaloids have some roles for anti-dementia effects. Less

慢性脑灌注灌注的大鼠是由双侧共同胡萝卜素动脉永久闭塞（2vo）产生的，是研究痴呆症的有用模型。 2vo大鼠在大脑的白质中暴露了学习和记忆行为和组织学罕见的损害。为了隔离诱导痴呆和稀疏性的大脑中的内在因子，将差异显示方法（DD）应用于从2VO和假手术大鼠大脑中分离出的mRNA 4天。检测到表达式的一个巨大变化的因素之一，并命名为VOF-21。尽管DD澄清的序列仅为415 nt，但也倾斜了VOF-21、4,885 NT的整个序列。 VOF-21序列是一部小说，该序列已提交给AB089205号Gene Bank。该表达式在2VO后7天显示峰值，然后在35天时降至假水平。该表达在大脑中很丰富，肺部随后在胸腺中。 Si…更多的Tu杂交结果表明，大脑中的表达富含Coreuleus，蓬丁核和海马。 RT/PCR表明NG108-15细胞中也存在VOF-21 mRNA。为了抑制该细胞中的表达，建立并报告了pH敏感的脂质体方法的条件。 VOF-21的功能意义仍在使用该脂质体系统，尤其是在CA2+和其他离子通道和/或迁移率上进行研究。几项研究表明，在动物模型中，未经芳烃种类的某些氧烷生物碱具有改善和神经保护作用。因此，通过使用电生理系统来阐明神经药物作用的潜在机制，研究了UNCAIA生物碱对神经递质受体功能的影响。结果表明，戊酸碱生物碱（肺炎和异端磷灰石）增强了在异北卵母细胞注射的脑RNA中由M1和5-HT2受体激活诱导的电生理反应。另一方面，四环氧烷生物碱（Rhynchophophyline和isorhynchophophylline）抑制了NMDA反应。众所周知，毒蕈碱受体抑制和NMDA受体刺激分别诱导痴呆和神经元细胞死亡。氧吲哚生物碱的这些机制在抗痴呆作用方面具有一些作用。较少的

项目成果

張紹輝 他: "一過性虚血及び抗コリン薬スコポラミン誘発の学習障害に対する四物湯の改善作用及び処方解析"Journal of Traditional Medicines. 18. 133-139 (2001)

张绍辉等：“下津对短暂性脑缺血和抗胆碱能药物东莨菪碱所致学习障碍的改善作用及处方分析”传统医学杂志 18. 133-139 (2001)。

Kang T.H. et al.: "Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes."Eur. J. Pharmacol.. 455. 27-34 (2002)

康同华

Sukma M. et al.: "CNS inhibitory effects of barakol, a constituent of Cassia siamia Lamk"Journal of Ethnopharmacology. 83. 87-94 (2002)

Sukma M.等人：“决明子成分巴拉科尔的中枢神经系统抑制作用”民族药理学杂志。

Dong E et al.: "Diazepam binding inhibitor (DBI) reduces testosterone and estradiol levels in vivo."Life Sciences.. 70. 1317-1323 (2002)

Dong E 等人：“地西泮结合抑制剂 (DBI) 降低体内睾酮和雌二醇水平。”Life Sciences.. 70. 1317-1323 (2002)

Kang T. H et al: "Pteropodine and isopteropodine positively modulate the function of rat muscarinic M_1 and 5-HT_2 receptors expressed in Xenopus oocyte."Eur. J. Pharmacol.. 444. 39-45 (2002)

Kang T. H 等人：“Pteropodine 和 isopteropodine 正向调节非洲爪蟾卵母细胞中表达的大鼠毒蕈碱 M_1 和 5-HT_2 受体的功能。”Eur.