磷酸二酯酶4作为抗抑郁药物作用靶点的研究

Phosphodiesterase 4( PDE4) :a novel target for the treatment of depression

磷酸二酯酶(PDEs)是体内水解第二信使环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)的酶类,磷酸二酯酶4(PDE4)是PDEs大家族的成员之一,目前其抑制剂在临床上主要用于治疗呼吸系统疾病及银屑病等。越来越多的研究表明PDE4参与抑郁症的发病机制,动物实验及临床试验均证实PDE4抑制剂具有良好的改善抑郁样症状的作用,PDE4抑制剂能够通过调控细胞内cAMP水平,活化cAMP/PKA/CREB及Epac/ERK等信号通路,从而改善抑郁症状。但是几乎所有的非选择性抑制剂都会产生严重的胃肠道反应,限制了该类药物的临床使用。因此,需要弄清PDE4抑制剂致呕吐作用的确切机制,开发出新型PDE4抑制剂;特异性PDE4亚型选择性抑制剂、变构调节剂及PDE4负性突变将是PDE4抑制剂研究的重点方向。

Phosphodiesterase（ PDE） is an enzyme responsible for the hydrolysis of second messengers cAMP and cGMP in various biological systems,particularly in the central nervous system（ CNS）.Phosphodiesterase 4（ PDE4） is a member of the PDE superfamily and its inhibitors are mainly used for the treatment of chronic obstructive pulmonary disease,asthma and psoriasis.In the CNS,an increasing number of researches have shown that PDE4 plays a key role in the process of major depressive disorder.PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain,and thus activate both PKA /CREB and Epac /ERK signal pathways.However,the serious side effects（ such as emesis and nausea）hinder its clinical application.There is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders.Approaches for the next generation of PDE4 inhibitors may include selective PDE4 subtype inhibitors,allosteric modulators and displacement of PDE4 s from macromolecular signaling complexes.