THE STUDY OF THE THERAPEUTIC MECHANISMS OF ANTIDEPRESSANT ON NEURONAL REMODELING

抗抑郁药对神经元重塑的治疗机制研究

• 批准号: 14570943
• 负责人: YAMADA Mitsuhiko
• 金额: $ 2.24万
• 依托单位: SHOWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570943/
• 关键词: antidepressant; neuroplasticity; rat; brain; gene; molecular biology; differential cloning; microarray; Differential Cloning

We have previously identified 200 cDNA fragments as antidepressant related genes (ADRG) from rat frontal cortex and hypothalamus using differential cloning technique. In the present study, we continued this screening in rat hippocampus and identified total of 707 cDNA and developed the ADRG microarray. More recently, we used ADRG microarray to search for s**e genes commonly induced after chronic antidepressant treatment and repeated ECT. ECT is another therapy for depressive patients that is widely used, particularly in the treatment of patients who are resistant to antidepressant medications. Interestingly, we found some genes related to neurite outgrowth, were commonly induced or decreased after chronic antidepressant treatment and repeated ECT. Thus, the unknown candidate ADRG genes may be thought that belong to the function related to the neurite outgrowth. ADRG#102 and ADRG#123 were subcloned to GFP expression vector and transfected to NGF-induced differentiated PC12 cels. Measurement of the morphological changes demonstrated that the mean length of the longest neurite in each cell and the total length of neurites per cell was significantly shorter in the transfectants, respectively. In addition, the mean neurite number per cell was also significantly smaller in the transfectants. One of the long-term therapeutic action of antidepressant may be related to the changes of both functional and structural neuroplasticity.

本研究利用差异克隆技术从大鼠额叶皮层和下丘脑中克隆了200个抗抑郁相关基因（ADRG）的cDNA片段。在本研究中，我们继续在大鼠海马中进行这种筛选，共鉴定了707个cDNA，并开发了ADRG芯片。最近，我们使用ADRG微阵列来寻找在慢性抗抑郁治疗和重复ECT后通常诱导的s**e基因。ECT是另一种广泛用于抑郁症患者的治疗方法，特别是用于治疗抗抑郁药物耐药的患者。有趣的是，我们发现一些与神经突起生长相关的基因，在慢性抗抑郁药治疗和反复ECT后通常被诱导或减少。因此，未知的候选ADRG基因可能被认为属于与神经突起生长相关的功能。将ADRG#102和ADRG#123亚克隆到GFP表达载体中，并转染到NGF诱导的分化的PC12细胞中。形态学变化的测量表明，每个细胞中最长的神经突的平均长度和每个细胞中神经突的总长度分别在转染子中显著缩短。此外，每个细胞的平均神经突数也显着较小的转染。抗抑郁药的长期治疗作用之一可能与功能和结构神经可塑性的改变有关。

项目成果

Nishioka.G.et al.: "Induction of kf-1 after repeated electroconvulsive treatment and chronic antidepressant treatment in rat frontal cortex and hippocampus"J. Neural. Trans.. (in press). (2003)

Nishioka.G.等人：“大鼠额叶皮层和海马重复电休克治疗和长期抗抑郁治疗后 kf-1 的诱导”J。

Yamada et al.: "Antidepressant-elicited changes in gene expression -Remodeling of neuronal circuits as a new hypothesis for drug efficacy."Prog Neuropsychopharmacol Biol Psychiatry. in press. (2004)

Yamada 等人：“抗抑郁药引发基因表达变化 - 神经元回路重塑作为药物功效的新假设。”Prog Neuropsychopharmacol Biol Psychiatry。

Yamada et al.: "Differential expression of VAMP2/synaptobrevin-2 after antidepressant and electroconvulsive treatment in rat frontal cortex"Pharmacogenomics J.. 2. 277-382 (2002)

Yamada 等：“大鼠额叶皮层抗抑郁药和电惊厥治疗后 VAMP2/synaptobrevin-2 的差异表达”Pharmacogenomics J.. 2. 277-382 (2002)

Nishioka et al.: "Induction of kf-1 after repeated electroconvulsive treatment and chronic antidepressant treatment in rat frontal cortex and hippocampus."J.Neural.Trans.. 110. 277-285 (2003)

Nishioka 等人：“大鼠额叶皮层和海马重复电惊厥治疗和慢性抗抑郁治疗后 kf-1 的诱导。”J.Neural.Trans.. 110. 277-285 (2003)

Yamada et al.: "Antidepressant research in the era of functional genomics - Farewell to the monoamine hypothesis-"Biogenic Amines. in press. (2004)

山田等人：《功能基因组学时代的抗抑郁研究——告别单胺假说——》生物胺。