Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System.
Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System.
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DOI：
10.1038/srep40115
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发表时间：
2017-01-05
影响因子：
4.6
通讯作者：
O'Donnell JM
中科院分区：
文献类型：
--
作者：
Zhang C;Xu Y;Zhang HT;Gurney ME;O'Donnell JM
抑制环磷酸腺苷(CAMP)特异性的磷酸二酯酶4(PDE4)被认为是一种潜在的治疗一系列神经心理疾病的方法，如抑郁、焦虑和记忆丧失。然而，每种PDE4亚型(PDE4A、4B和4C)在不同类别的行为中的具体参与尚不清楚。在本研究中，我们比较了PDE4B和PDE4D选择性抑制剂A-33和D159687在调节小鼠神经功能方面的可能药理作用。这两种化合物在刺激小鼠海马细胞系HT-22中的cAMP信号，导致CREB磷酸化增加方面都是同样有效的。相反，A-33和D159687在小鼠行为测试中显示出明显的神经药理作用。A-33具有抗抑郁剂样的轮廓，在强迫游泳和尾部悬挂任务中减少了不动时间，以及在新奇抑制喂养测试中减少了喂养延迟。另一方面，D159687在新颖的物体识别测试中改善了记忆，但没有抗抑郁或缓解焦虑的好处，因此具有先兆特征。目前的数据表明，针对特定PDE4亚型的抑制剂可能表现出不同的药理作用，并有助于对神经心理疾病进行更有效的药物治疗。
Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions.
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影响因子：
4.8
作者：
Fox D 3rd;Burgin AB;Gurney ME
通讯作者：
Gurney ME
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：
14.8
作者：
Leger, Marianne;Quiedeville, Anne;Freret, Thomas
通讯作者：
Freret, Thomas
影响因子：
4.5
作者：
Fatemi, S. Hossein;King, David P.;Menniti, Frank S.
通讯作者：
Menniti, Frank S.
影响因子：
2.7
作者：
Bourin, M;Chenu, F;David, DJP
通讯作者：
David, DJP