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The involvement of the BDNF signal transduction to the pathogenesis of ssstress-related psychiatric disorders

BDNF 信号转导参与 ssstress 相关精神疾病的发病机制

基本信息

批准号：
07671046
负责人：
MORINOBU Shigeru
金额：
$ 1.47万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

To elucidate the involvement of the dysfunction of the BDNF signal transduction to the pathogenesis of stress-related psychiatric illnesses including depression, at first, the influence of various chronic stress paradigms on the expression of BDNF and trkB mRNA, and the activity of mitogen activated protein (MAP) kinase was examined in rat frontal cortex and hippocampus. In second, the effect of co-administration of a phosphodiesterase IV (PDE4) inhibitor on the induction of the BDNF signal transduction by antidepressant treatments, and NKH477 (water-soluble forskolin derivative) administration on the BDNF signal transduction were determined. Various acute and chronic stress paradigms significantly decreased the expression of BDNF and trkB mRNA in rat brain. While both acute and chronic restraint stress significantly increased the activity of MAP kinase in rat brain mediately after stress, both stress paradigms did not change the activity of MAP kinase i or 3 h after stress. The co-administration of a PDE4 inhibitor with an antidepressant as well as NKH477 administration significantly induced the expression of BDNF and trkB mRNA, and the increase in MAP kinase activity in rat brain. This co-administration (7 days) and NKH477 administration (1 h) shortened the time required for the significant induction of BDNF and trkB mRNA by antidepressant treatments (21 days). The results of this study may indicate that the decrease in BDNF mRNA expression by stress dose not affect the postsynaptic BDNF signa transductiorn However, it is possible that the enhancement of MAP kinase activity by stress may mask the decrease in MAP kinase activity due to the reduction of BDNF and trkB expression. The present results indicating the activation of the BDNF signal transduction by this co-administration and NKH477, raise the possibility that the stimulation of the cAMP signal transduction may have potential as a novel pharmacotherapy for depression.

为阐明脑源性神经营养因子信号转导功能障碍在抑郁症等应激相关精神疾病发病机制中的作用，首先观察了不同慢性应激方式对大鼠额叶皮质和海马区脑源性神经营养因子和TrkB基因表达及丝裂原活化蛋白(MAP)激酶活性的影响。其次，研究了联合应用磷酸二酯酶IV(PDE4)抑制剂和NKH477对抗抑郁药诱导的BDNF信号转导的影响，以及NKH477对BDNF信号转导的影响。不同的急、慢性应激方式均可显著降低大鼠脑内BDNF和TrkB的表达。急性和慢性束缚应激均可使大鼠脑内MAP-K活性在应激后中途显著升高，但在应激后3h和应激后3h，两种应激模式对MAP-K I活性均无明显影响。PDE4抑制剂与抗抑郁药联合应用以及NKH477均可显著诱导大鼠脑内BDNF和TrkB mRNA的表达以及MAP激酶活性的升高。这种联合给药(7天)和NKH477给药(1小时)缩短了抗抑郁治疗显著诱导BDNF和TrkB mRNA所需的时间(21天)。本研究结果可能提示，应激引起的BDNF mRNA表达下降并不影响突触后BDNF信号转导，但应激引起的MAP激酶活性的增强可能掩盖了由于BDNF和TrkB表达减少而导致的MAP激酶活性的降低。本研究结果表明，联合给药和NKH477可激活BDNF信号转导通路，提示刺激cAMP信号转导通路有可能成为治疗抑郁症的一种新的药物治疗方法。