Study on the role of ethanol-induced apoptosis and signal transduction system in the pathophysiology of alcohol/drug dependence.

乙醇诱导的细胞凋亡及信号转导系统在酒精/药物依赖病理生理学中的作用研究。

• 批准号: 12670950
• 负责人: SAITO Toshikazu
• 金额: $ 2.11万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670950/
• 关键词: alcohol; dependence; cellular signal transduction; Ca^<2+>; CREB; annexin; apoptosis; postmortem brain; 薬物

Our previous studies suggest that the quantitative and qualitative reduction of certain G proteins and type I adenylyl cyclase (AC-I) are related to the features of human alcoholics, indicating that cAMP-mediated signal transduction is disordered in alcoholic brain. Since cAMP-regulated gene transcription via CREB has been demonstrated to have a crucial role in the brain function, we investigated the amounts of both CREB and its phosphorylated form in the postmortem human brains. Although the amount of neither CREB nor phosphorylated CREB significantly changed in the alcoholic brains regardless of the different regions compared to controls, further investigation is needed to elucidate the molecular mechanism for the alteration of cAMP-mediated signal transduction in alcoholics. On the other hand, it has also been pointed out that sever alcoholics are often accompanied with a brain atrophy via a disorder of cellular Ca^<2+>-system. Annexin IV, a Ca^<2+> /lipid binding protein, was signi … More ficantly augmented in amount in the postmortem brains (the hippocampus) of alcoholics. In addition, the alcoholic patients tended to have autoantibodies to annexin IV. Using cultured cells (rat glioma C6 cells and human adenocarcinoma A549 cells), it was shown that the intrinsic amount of annexin IV was increased by the exposure to ethanol in the both cells, whereas levels of annexins I and V were unchanged. The mitochondrial dehydrogenae activity, which is an index for monitoring cell lesion (apoptosis), was decreased and caspase 3 activity was increased with a high concentration of ethanol (200 mM or more) after 12 or 24h-exposure, but the amount of annexin IV was increased even with a low concentration of ethanol (50 mM) at which cell damage had not been induced. Interestingly, the overexpression of annexin IV in C6 cells by transfection with annexin IV-DNA enhanced ethanol-induced cell lesion and was accompanied by NFkB activation. Thus, it might be indicated that the amount of annexin IV is selectively augmented and this augmentation facilitates the development of cell lesion by ethanol. Less

我们的前期研究表明，某些G蛋白和I型腺苷酸环化酶（AC-I）的定量和定性降低与人类酒精中毒的特征有关，提示酒精中毒脑内cAMP介导的信号转导紊乱。由于cAMP通过CREB调控的基因转录已被证明在脑功能中起着至关重要的作用，我们研究了CREB及其磷酸化形式在死后人脑中的含量。尽管与对照组相比，无论在不同区域，酒精性脑中CREB和磷酸化CREB的量都没有显著变化，但需要进一步研究以阐明酒精性脑中cAMP介导的信号转导改变的分子机制。另一方面，也有人指出，严重的酗酒者往往伴随着脑萎缩，通过细胞Ca^<2+>-系统的障碍。膜联蛋白IV是一种钙/脂质结合蛋白，与正常人相比， ...更多信息 酗酒者死后大脑（海马体）中的含量增加。此外，酒精中毒患者往往有自身抗体膜联蛋白IV。使用培养的细胞（大鼠神经胶质瘤C6细胞和人腺癌A549细胞），结果表明，膜联蛋白IV的固有量增加了在两种细胞中的乙醇暴露，而膜联蛋白I和V的水平不变。在暴露12或24小时后，高浓度乙醇（200 mM或更高）降低了作为监测细胞损伤（凋亡）的指标的线粒体膜酶活性，并且增加了半胱天冬酶3活性，但是即使在未诱导细胞损伤的低浓度乙醇（50 mM）下，膜联蛋白IV的量也增加了。有趣的是，通过用膜联蛋白IV-DNA转染C6细胞中膜联蛋白IV的过表达增强了乙醇诱导的细胞损伤，并伴随着NF κ B活化。因此，可能表明膜联蛋白IV的量被选择性地增加，并且这种增加促进了乙醇引起的细胞损伤的发展。少

项目成果

齋藤利和: "標準精神医学"医学書院. 20 (2001)

齐藤俊和：《标准精神病学》《医学书院》20 (2001)。

Yamamoto, M. et al.: "Immunoreactivity of cAMP response element binding protein is not altered in the post-mortem cerebral cortex or cerebellum of alcoholics."Alcohol and Alcoholism. 36. 70-74 (2001)

Yamamoto, M. 等人：“酗酒者死后大脑皮层或小脑中 cAMP 反应元件结合蛋白的免疫反应性没有改变。”酒精和酒精中毒。

Pandey, S. C. et al.: "cAMP signaling cascade : a promising role in ethanol tolerance and dependence."Alcohol Clin Exp res. 25. 46S-48S (2001)

Pandey, S. C. 等人：“cAMP 信号级联：在乙醇耐受性和依赖性中具有前景的作用。”Alcohol Clin Exp res。

Shichinohe, S. et al.: "Changes in the cAMP-related signal transduction mechanism in postmortem human brains of heroin addicts."J Neural Transm. 108. 335-347 (2001)

Shichinohe, S. 等人：“海洛因成瘾者死后大脑中 cAMP 相关信号转导机制的变化。”J Neural Transm。

Sohma, H. et al.: "Ethanol-induced augmentation of annexin IV expression in C6 glioma and A549 adenocarcinome cells."Alcohol Clin Exp Res. (in press).

Sohma, H. 等人：“乙醇诱导 C6 神经胶质瘤和 A549 腺癌细胞中膜联蛋白 IV 表达的增强。”Alcohol Clin Exp Res。