Long-term effects of intracerebral bioactive substances

脑内生物活性物质的长期影响

• 批准号: 04304037
• 负责人: KITO Shozo
• 金额: $ 12.16万
• 依托单位: THE UNIVERSITY OF THE AIR
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Co-operative Research (A)
• 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/grant/KAKENHI-PROJECT-04304037/
• 关键词: long-term effects; protooncogenes; nicotine; long-term potentiation; GABA receptor; excitatory amino acids; substance P; kinase IV; dexamethasone; NO 合成酵素; 長期増強; DBI mRNA; Myc; CABA^A受容体; c-fos; GABAAα1サブユニットmRNA; AP-1; interleukin-1β; z

It has been known that cell stimulation by growth factors and hormones often causes changes of gene expression which lead to long-term effects of cell response.Much attentions have been forcused on this kind of responses from viewpoints of basic and clinical pharmacology. The particularly important is that several kinds of protooncogenes are participated in chemical signal transduction as well as mechanism of drug addiction.In this study, mechanisms of cell responses evoked by various neuroactive substances in the central nervous system were investigated from viewpoints of chemistry, molecular biology, electrophysiology and morphology and following results were obtained. (1) Nicotine inhibited dexamethasoneinduced kainic acid cytotoxcity dose-dependently. On the other hand, single injection of estrogen into rat caused cytoprotection of amygdala neurons at lower doses and cytotoxicity at higher doses. (2) By means of electrophsiologcal studies using hippocampal slices, it was found that … More cholinergic regulation is participated in long-term potentiation at mossy fiber-CA3 synapes. (3) Changes of intracellular GABA receptor structure due to alcoholic addiction was studied. As the results, alcoholic addiction caused changes of both GABA_A and GABA_B receptors. It was assumed that such disorders of suppressive function are connected to development of alcoholic abstinence. (4) Mechanism of long-term effects of excitatory amino acids in the brain was studied from viewpoints of gene transduction. (5) Expression of mRNA of gamma1 and gamma2 subunit of GABA_A receptors and AMPA type glutamic acid receptors, Glu R1, 2 were examined in the dorsal root ganglion neurons and spinal dorsal horn neurons. (6) To examine substance P's effect on the brain, mechanism of substance P receptor expression was examined using U-87 MG cells. (7) Effect of pentylentetrazole and kainic acid administration on various gene expression in the hippocampus was studied. (8) Expression of c-fos mRNA induced by cycolohexamide was inhibited by cenelifide. (9) Kinase IV was purfied from rat brain. This kinase was found to be a multifunctional protein kinase specifically distributed in the brain. Less

众所周知，生长因子和激素对细胞的刺激往往会引起基因表达的改变，从而导致细胞反应的长期影响。从基础药理学和临床药理学的角度对这类反应已引起了广泛的关注。特别重要的是，几种原癌基因参与了药物成瘾的化学信号转导和机制。本研究从化学、分子生物学、电生理学和形态学等方面探讨了中枢神经系统各种神经活性物质诱发细胞反应的机制，得到了以下结果：(1)烟碱对地塞米松诱导的卡因酸细胞毒性有剂量依赖性抑制作用。另一方面，单次注射雌激素对大鼠杏仁核神经元具有低剂量的细胞保护作用，高剂量的细胞毒性作用。(2)通过海马体切片电生理研究发现，苔藓纤维- ca3突触参与长时程增强的胆碱能调节更多。(3)研究了酒精成瘾对细胞内GABA受体结构的影响。结果表明，酒精成瘾引起GABA_A和GABA_B受体的改变。人们认为这种抑制功能障碍与戒酒的发展有关。(4)从基因转导的角度研究了兴奋性氨基酸在脑中的长期作用机制。(5)检测GABA_A受体γ - 1、γ - 2亚基和AMPA型谷氨酸受体Glu R1、2 mRNA在背根神经节神经元和脊髓背角神经元中的表达。(6)为探讨P物质对脑的影响，采用U-87 MG细胞检测P物质受体的表达机制。(7)研究戊四唑和kainic酸给药对海马各基因表达的影响。(8)环己甲胺诱导的c-fos mRNA表达被百里lifide抑制。(9)从大鼠脑中纯化激酶IV。该激酶被发现是一种特异性分布于大脑的多功能蛋白激酶。少

项目成果

Miyoshi, R., Fujii, E., Muraki, T.and Kito, S.: "Effect of estrogen on immediate early gene expression in the rat brain." Society for Neuroscience Abstracts. 18. 57.1 (1992)

Miyoshi, R.、Fujii, E.、Muraki, T. 和 Kito, S.：“雌激素对大鼠大脑立即早期基因表达的影响”。

Minami,M.: "Cloning and expression of a cDNA for the rat κ-opioid receptor." FEBS Letters. 329. 291-295 (1993)

Minami, M.：“大鼠 κ-阿片受体 cDNA 的克隆和表达。” 329. 291-295 (1993)

Ogita,K.: "Inhibition by calmodulin antagonists of〔^3H〕MK-801 binding in brain synaptic membranes." Journal of Neurochemistry. 59. 1008-1016 (1992)

Ogita, K.：“钙调蛋白拮抗剂对脑突触膜中 MK-801 结合的抑制。” 神经化学杂志 59. 1008-1016 (1992)

Ogo,H.: "Modulation of substance p receptor in human astrocytoma cells by antisense oligodeoxynucleotides." General Pharmacology. in press. (1994)

Ogo,H.：“通过反义寡脱氧核苷酸调节人星形细胞瘤细胞中的 p 物质受体。”

Kameshita,I.: "Autophosphorylation of calmodulin-dependent protein kinase IV from rat cerebral cortex^1." J.Biochem.113. 583-590 (1993)

Kameshita,I.：“大鼠大脑皮层钙调蛋白依赖性蛋白激酶 IV 的自磷酸化^1。”