Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice.
Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice.
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前额皮质中磷酸二酯酶 4D 的敲低可减轻小鼠慢性不可预测的压力诱发的抑郁样行为和记忆缺陷。
DOI：
10.1038/srep11332
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发表时间：
2015-07-10
影响因子：
4.6
通讯作者：
Li YF
中科院分区：
文献类型：
--
作者：
Wang ZZ;Yang WX;Zhang Y;Zhao N;Zhang YZ;Liu YQ;Xu Y;Wilson SP;O'Donnell JM;Zhang HT;Li YF
磷酸二酯酶4（PDE 4）有四种亚型（PDE 4A-D），至少有25种剪接变体。PDE 4亚型非选择性抑制剂通过增加脑中的细胞内环AMP（cAMP）信号传导产生有效的抗抑郁样和认知增强作用。我们以前的数据表明，长型PDE 4D似乎参与了正常动物中PDE 4抑制剂的这些药理学特性。然而，目前尚不清楚长型PDE 4D是否对抑郁动物的行为和相关的细胞信号传导/神经元可塑性/神经内分泌改变至关重要。在本研究中，动物暴露于慢性不可预测的压力（CUS），抑郁症的啮齿动物模型，表现出升高的皮质酮，抑郁样行为，记忆缺陷，伴随着减少cAMP-PKA-CREB和cAMP-ERK 1/2-CREB信号和神经可塑性。CUS诱导的这些改变被RNA干扰（RNAi）介导的前额叶皮层长型PDE 4D（特别是PDE 4D 4和PDE 4D 5）敲低逆转，类似于PDE 4亚型非选择性抑制剂咯利普兰的作用。此外，RNA干扰的这些作用不被咯利普兰增强。这些数据表明，长型PDE 4D在PDE 4抑制剂治疗抑郁症和伴随的记忆缺陷的药物治疗中具有主导作用。长型PDE 4D，特别是PDE 4D 4和PDE 4D 5，似乎是开发具有高治疗指数的抗抑郁药的有希望的靶点。
Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.
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DOI：
10.1523/jneurosci.5236-10.2011
发表时间：
2011-01-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li YF;Cheng YF;Huang Y;Conti M;Wilson SP;O'Donnell JM;Zhang HT
通讯作者：
Zhang HT
影响因子：
3.7
作者：
Ibarguen-Vargas, Yadira;Surget, Alexandre;Belzung, Catherine
通讯作者：
Belzung, Catherine
DOI：
10.1016/j.ijdevneu.2011.02.006
发表时间：
2011-05
影响因子：
1.8
作者：
Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
影响因子：
4.8
作者：
Atkinson, HC;Waddell, BJ
通讯作者：
Waddell, BJ
影响因子：
3.3
作者：
Flores, G;Alquicer, G;Srivastava, LK
通讯作者：
Srivastava, LK