Graduate Program in Pharmaceutical and Pharmacological Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA.
J Pharmacol Exp Ther. 2011 Aug;338(2):641-7. doi: 10.1124/jpet.111.179358. Epub 2011 May 12.
The effects of repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine (CDP840), which differ in their interactions with high- and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cAMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1 and 3 mg/kg), piclamilast (0.3 and 1 mg/kg), or CDP840 (10 and 30 mg/kg) for 16 days increased cAMP and phosphorylation of cAMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cAMP and pCREB in hippocampus and prefrontal cortex, but the dose and time dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, probably because of its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cAMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.
重复治疗磷酸二酯酶 4（PDE4）抑制剂罗利普兰、匹立米特和 4-（2-（3-（环戊氧基）-4-甲氧基苯基）-2-苯乙基）吡啶（CDP840）的效果，这些抑制剂在与酶的高亲和性和低亲和性结合构象体的相互作用方面存在差异，与急性治疗在大鼠 cAMP 信号、海马细胞增殖和强迫游泳试验中的不动性方面的效果进行了对比。重复治疗罗利普兰（1 和 3 mg/kg）、匹立米特（0.3 和 1 mg/kg）或 CDP840（10 和 30 mg/kg）16 天，增加了海马体和前额叶皮层中的 cAMP 和 cAMP 反应元件结合蛋白（pCREB）的磷酸化。此外，PDE4 抑制剂的重复治疗增加了海马体中新细胞的增殖和存活，并产生了抗抑郁样作用，表现在强迫游泳试验中不动性的减少。急性治疗罗利普兰（3 mg/kg）、匹立米特（1 mg/kg）或 CDP840（30 mg/kg）诱导了海马体和前额叶皮层中 cAMP 和 pCREB 的短暂增加，但这些作用的剂量和时间依赖性与行为作用不平行。与罗利普兰和匹立米特相比，CDP840 的重复治疗对神经和行为测量的影响较小，可能是因为它与 PDE4 的高亲和性结合构象体的相互作用较弱。这表明高亲和性结合构象体在 PDE4 抑制对 cAMP/pCREB 信号、海马体细胞增殖和抗抑郁样行为作用的长期影响中的相对重要性。
