Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Sci Rep. 2017 Jan 5;7:40115. doi: 10.1038/srep40115.
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.
抑制环腺苷酸（cAMP）特异性磷酸二酯酶 4（PDE4）被认为是治疗一系列神经心理疾病的潜在方法，如抑郁症、焦虑症和记忆力减退。然而，每种 PDE4 亚型（PDE4A、4B 和 4C）在不同行为类别中的具体参与作用尚未阐明。在本研究中，我们比较了 PDE4B 和 PDE4D 选择性抑制剂 A-33 和 D159687 在介导小鼠神经功能中的可能药理学效应。这两种化合物在刺激 HT-22 小鼠海马细胞系中的 cAMP 信号方面同样有效，导致 CREB 磷酸化增加。相比之下，A-33 和 D159687 在小鼠行为测试中表现出不同的神经药理学效应。A-33 具有抗抑郁样特征，表现在强迫游泳和悬尾任务中不动时间减少，以及新颖性抑制进食测试中进食潜伏期减少。另一方面，D159687 具有认知促进作用，因为它改善了新物体识别测试中的记忆，但没有抗抑郁或抗焦虑作用。本数据表明，针对特定 PDE4 亚型的抑制剂可能表现出不同的药理学效应，并有助于针对神经心理疾病的更有效的药物治疗。
