Antidepressants and Fibroblast Growth Factor

抗抑郁药和成纤维细胞生长因子

基本信息

批准号：
7051426
负责人：
Italo Mocchetti
金额：
$ 15.16万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-09 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The mechanism(s) responsible for the therapeutic effect of antidepressant drugs is not completely understood. One current view regarding the pathology of depression proposes that this mental illness results from dysfunction of synaptic connections, perhaps due to the loss of synaptic contacts. Conversely, recent experimental data have suggested that the therapeutic action of antidepressants may involve their ability to increase neurogenesis and synaptic strength. These properties may result more from the induction of neurotrophic factor synthesis than activation of monoamine receptors. This suggestion is supported by preliminary data showing that antidepressants increase the synthesis of basic fibroblast growth factor (FGF2), a neurotrophic factor that exerts neurotrophic activity on catecholaminergic neurons and promotes neurogenesis in the adult brain. These experimental data give rise to a novel and challenging but timely hypotheses that depression is characterized by lack of trophic support and that antidepressants restore synaptic plasticity in adult brain by inducing the synthesis of FGF2. As an experimental tool to test these hypotheses, we propose to use a rat model of depression termed chronic, unpredictable mild stress (CMS), by which rats develop anhedonia, one of the core symptoms of major depression. In particular, we plan to investigate whether CMS down-regulates FGF2 expression (mRNA and protein) in the brain and whether antidepressants such as desipramine and fluoxetine will reverse this down-regulation. Moreover, since CMS evokes apoptotic cell death in the frontal cortex, we propose to test the neuroprotective activity of antidepressants in this animal model of depression by examining the ability of antidepressants and FGF2 to limit apoptotic cell death. Apoptosis will be determined by measuring caspase- 3 activation and in situ terminal deoxynucleotidyl transferase-mediated biotinylated DTP nick end labeling (TUNEL) staining in several brain areas of CMS rats. Overall, the results of the present study will provide a major break-through on the mechanisms whereby antidepressants affect neuronal plasticity in mature rats. Data from this proposal may help elucidate the therapeutic efficacy of antidepressants in affective disorders.

描述（由申请人提供）：尚不完全了解负责抗抑郁药治疗作用的机制。关于抑郁病理学的一种当前观点提出，这种精神疾病是由于突触连接功能障碍引起的，这可能是由于突触接触的丧失所致。相反，最近的实验数据表明，抗抑郁药的治疗作用可能涉及其提高神经发生和突触强度的能力。与单胺受体的激活相比，神经营养因子合成的诱导可能更多。这一建议得到了初步数据的支持，表明抗抑郁药增加了基本成纤维细胞生长因子（FGF2）的合成，这是一种神经营养因子，在Catecholamin能力神经元上发挥神经营养活性，并促进成人大脑的神经发生。这些实验数据引起了一种新颖而挑战但及时的假设，即抑郁症的特征是缺乏营养支持，并且抗抑郁药通过诱导FGF2的合成来恢复成人大脑中的突触可塑性。作为检验这些假设的实验工具，我们建议使用一种称为慢性，不可预测的轻度压力（CMS）的大鼠模型，通过该模型，大鼠会出现Anhedonia，这是严重抑郁症的核心症状之一。特别是，我们计划研究CMS在大脑中下调FGF2表达（mRNA和蛋白质）是否是否会抗抑郁和氟西汀等抗抑郁药会逆转这种下调。此外，由于CMS唤起了额叶皮质中的凋亡细胞死亡，因此我们建议通过检查抗抑郁药和FGF2限制凋亡细胞死亡的能力，以测试这种抑郁症动物模型中抗抑郁药的神经保护活性。凋亡将通过测量caspase 3激活和原位末端脱氧核苷酸转移酶介导的生物素化DTP nick端标记（TUNEL）染色（TUNEL）在CMS大鼠的几个大脑区域中。总体而言，本研究的结果将为抗抑郁药影响成熟大鼠的神经元可塑性的机制提供重大突破。该提案的数据可能有助于阐明抗抑郁药在情感障碍中的治疗功效。