Studies on the molecular biology of the relationship between neurotrophin which functions to central nervous system (CNS) and Alzheimer's disease (AD)

中枢神经系统（CNS）神经营养素与阿尔茨海默病（AD）关系的分子生物学研究

• 批准号: 04454257
• 负责人: HAYASHI Kyozo
• 金额: $ 4.29万
• 依托单位: Gifu Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04454257/
• 关键词: neurotrophic factor; Alzheimer's disease; coenzyme; nerve growth factor (NGF); enzyme immunoassay (EIA); astrocytes; forebrain-lesioned rat; NGF synthesis stimulation; interleukin; EIA; 神経成長因子(NGF); Alzheimer型老人痴呆症; 糖鎖; コリンアセチルトランスフェラーゼ(CAT)

(1)The coenzymes such as pyrroloquinoline quinone, lipoic acid, found to have the stimulatory effect of NGF synthesis without causing cytotoxicity. Especially, pyrroloquinoline quinone showed strong activity of pormoting NGF synthesis in mouse astrocytes, whereas lipoic acid has the stong effect on BALB c/3T3 cells.(2)6-(4-Hydroxybuty1)-2,3,5-trimethy1-1,4-benzoquinone (TMQ) stimulated NGF synthesis in astrocytes. The compound showeds improving effects on memory and choline acetyltransferase (CAT) activity in basal forebrain-lesioned rats, an amnesia animal model. TMQ ameliorated amnesia in the water maze and passive avoidance tanks. This compound not only restored the reduced CAT activity in the parietal cerebral cortex, but also increased NGF content and CAT activity in the hippocampus.(3)The NGF level using our enzyme immunoassay system for human NGF were found to be no difference in NGF level in serum, brain-spiral fliud, or brain (hippocampus and parietal cortex) obatained from no … More rmal people and patients with Alzheimer's disease.(4)In the stimulatory effect of alkylcatechols on NGF synthesis, neither PKC-dependent pathway nor cAMP-dependent pathway was dominant.(5)Interleukin (IL)-2 supported the servival and enhanced neurite extention of cultured hippocampal neurons prepared from embryonic 18-day-old rats. IL-2 also supported the survival of cultured cortical, striatal, and septal ieurons. These results indicate that IL-2 has a survival-promoting effect on a wide variety of neurons.(6)IL-4 and IL-5 singifiantly increased the amounts of NGF secreted by mouse astrocytes, whereas IL-2, IL-3, and IL-6 had no significant effect. IL-4 and IL-5 showed marked increases in NGFmRNA levels in astrocytes as demonstrated by the reverse transcription-polymerase chain reaction (RT-PCR) method. The effect of IL-4 and IL-5 was greater in quiescent astrocytes than in growing cells.(7)Denervation of depaminergic neurons by intra nigra injection of 6-hydroxydopamine (6-OHDA) increased NGF content in the cortex and hippocampus, both of which are innervated by cholinergic neurons. The increase continued during an observation period of 0.5-28 days after the lesion. The time course of changes in NGF content was quite different from that of cholinergic neuron denervation. Less

(1)吡咯喹啉醌、硫辛酸等辅酶被发现具有刺激NGF合成的作用而不引起细胞毒性。特别是，吡咯并喹啉醌在小鼠星形胶质细胞中显示出强烈的促进 NGF 合成的活性，而硫辛酸对 BALB c/3T3 细胞具有强烈的作用。(2)6-(4-Hydroxybuty1)-2,3,5-trimethy1-1,4-苯醌 (TMQ) 刺激小鼠星形胶质细胞中的 NGF 合成。 星形胶质细胞。该化合物对基底前脑损伤的大鼠（一种失忆症动物模型）的记忆力和胆碱乙酰转移酶（CAT）活性有改善作用。 TMQ 改善了水迷宫和被动回避池中的健忘症。该化合物不仅恢复了顶叶大脑皮层中降低的CAT活性，而且还增加了海马中的NGF含量和CAT活性。(3)使用我们的人NGF酶联免疫分析系统检测到的NGF水平与从非正常人获得的血清、脑螺旋液或大脑（海马和顶叶皮质）中的NGF水平没有差异。 (4)在烷基儿茶酚对NGF合成的刺激作用中，PKC依赖性途径和cAMP依赖性途径都不占主导地位。(5)白细胞介素(IL)-2支持从18日龄大鼠胚胎培养的海马神经元的存活和增强的神经突延伸。 IL-2 还支持培养的皮质、纹状体和间隔神经元的存活。这些结果表明IL-2对多种神经元具有促进存活的作用。(6)IL-4和IL-5显着增加小鼠星形胶质细胞分泌的NGF量，而IL-2、IL-3和IL-6则无显着影响。逆转录聚合酶链式反应 (RT-PCR) 方法证明，星形胶质细胞中 IL-4 和 IL-5 的 NGFmRNA 水平显着增加。 IL-4和IL-5在静止星形胶质细胞中的作用比在生长细胞中更大。(7)通过黑质内注射6-羟基多巴胺(6-OHDA)去巴胺能神经元去神经，增加了皮层和海马中NGF的含量，这两个部位均受胆碱能神经元支配。在病变后0.5-28天的观察期内，这种增加持续存在。 NGF含量变化的时间过程与胆碱能神经元去神经支配的时间过程有很大不同。较少的

项目成果

K.Murase,T.Nabeshima,Y.Robitaille,R.Quirion,M.Ogawa,K.Hayashi: "NGF Level is not Decreased in the Serum,Brain-Spinal Fluid,Hippocampus,or Parietal Cortec of Individuals with Alzheimer's Disease." Biochem.Biophys.Res.Commun.193. 198-203 (1993)

K.Murase、T.Nabeshima、Y.Robitaille、R.Quirion、M.Okawa、K.Hayashi：“阿尔茨海默病患者的血清、脑脊髓液、海马或顶叶皮质中的 NGF 水平并未降低。

S.Inoue,K.Ikeda,K.Hayashi: "Elapidae Venoms.Toxin-Related Diseases" Oxford & IBH Publishing Co.,PVT,Ltd., 543 (1993)

S.Inoue、K.Ikeda、K.Hayashi：“Elapidae 毒液。毒素相关疾病”牛津

K.Murase, R.Takeuchi, E.Iwata, Y.Furukawa, S.Furukawa, and K.Hayashi: "Development Changes in Nerve Grwoth Factor Level in Rat Serum." J.Neurosci, Res.33. 282-288 (1992)

K.Murase、R.Takeuchi、E.Iwata、Y.Furukawa、S.Furukawa 和 K.Hayashi：“大鼠血清中神经生长因子水平的发展变化。”

K.Murase, H.Awatsuji, K.Hayashi, R.Nuydens, R.Nuyens, F.Cornelissen, and H.Greets: "Sabeluzole Potentiates the Effect of Nerve Growth Factor on Survival and Differentiation in PC12 Cells and Sympathetic Neurons." Neurodegeneration. 2. 173-181 (1993)

K.Murase、H.Awatsuji、K.Hayashi、R.Nuydens、R.Nuyens、F.Cornelissen 和 H.Greets：“Sabeluzole 增强神经生长因子对 PC12 细胞和交感神经元存活和分化的影响。”

K.Murase,Y.Murakami,K.Takayanagi,Y.Furukawa,K.Hayashi: "Human Fibroblast Cells Synthesize and Secrete Nerve Growth Factor in Culture" Biochem.Biophys.Res.Commun.184. 373-379 (1992)

K.Murase、Y.Murakami、K.Takayanagi、Y.Furukawa、K.Hayashi：“人类成纤维细胞在培养物中合成和分泌神经生长因子”Biochem.Biophys.Res.Commun.184。