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

为了阐明BDNF信号转导功能障碍在应激相关精神疾病（包括抑郁症）发病机制中的作用，本研究首先检测了不同慢性应激模式对大鼠额叶皮层和海马BDNF和trkB mRNA表达以及丝裂原活化蛋白激酶（MAP激酶）活性的影响。第二，测定了共同施用磷酸二酯酶IV（PDE 4）抑制剂对通过抗抑郁治疗诱导BDNF信号转导的影响，以及NKH 477（水溶性毛喉素衍生物）施用对BDNF信号转导的影响。各种急、慢性应激模式均可显著降低大鼠脑内BDNF和trkB mRNA的表达。急性和慢性束缚应激均可显著增加应激后大鼠脑组织MAP激酶的活性，但应激后1 h和3 h MAP激酶的活性均无明显变化。PDE4抑制剂与抗抑郁药的联合给药以及NKH 477给药显著诱导大鼠脑中BDNF和trkB mRNA的表达，以及MAP激酶活性的增加。这种共同给药（7天）和NKH 477给药（1小时）缩短了抗抑郁药治疗显著诱导BDNF和trkB mRNA所需的时间（21天）。本研究结果提示，应激引起的BDNF mRNA表达的降低并不影响突触后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表达的降低而引起的MAP激酶活性的降低。目前的结果表明，通过这种共同施用和NKH 477激活BDNF信号转导，提高了cAMP信号转导的刺激可能具有作为抑郁症的新药物疗法的潜力的可能性。

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.