Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice
Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice
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磷酸二酯酶 4 抑制剂依唑酯和磷酸二酯酶 5 抑制剂西地那非通过环 AMP 或环 GMP 信号传导对小鼠产生抗抑郁样作用
DOI：
10.1007/s11011-014-9533-4
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发表时间：
2014-09-01
影响因子：
3.6
通讯作者：
Zhang, Han-Ting
中科院分区：
文献类型：
--
作者：
Wang, Chuang;Zhang, Jianrui;Zhang, Han-Ting
抑制磷酸二酯酶-4或5（PDE 4或PDE 5）分别增加环磷酸腺苷（cAMP）或环磷酸鸟苷（cGMP），从而激活cAMP反应元件结合蛋白（CREB）/脑源性神经营养因子（BDNF）/神经肽VGF（非acryonimic）信号传导，并对行为产生抗抑郁样作用。然而，这些行动之间的因果关系尚未确定。在本研究中，在存在或不存在蛋白激酶A（PKA）或蛋白激酶G（PKG）抑制剂的情况下，通过侧脑室（i. c. v.）输液测定海马和前额叶皮质cAMP、cGMP含量及pCREB、CREB、BDNF和VGF表达。结果显示，依他唑酯5.0 mg/kg或西地那非30 mg/kg可显著逆转CNS诱导的抑郁样行为，其作用分别与cAMP/pCREB/BDNF/VGF或cGMP/pCREB/BDNF/VGF信号转导水平的增加相一致。这些影响完全消除后，PKA或PKG抑制，分别。结果表明，依他唑盐抑制PDE 4或西地那非抑制PDE 5可通过cAMP或cGMP信号通路（共享CREB/BDNF/VGF的共同下游信号通路），在CNS处理的动物中产生抗抑郁样作用。
Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF.