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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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Abstract

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.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81201050 to Dr. Chuang Wang; No. 30901802 to Dr. Xin Zhao); Natural Science Foundation of Zhejiang province (No. LQ12H09001 to Dr. Chuang Wang and No. LY12H09002 to Dr. Xin Zhao); Natural Science Foundation of Ningbo (No. 2012A610249 to Dr. Chuang Wang); Natural Science Foundation of Ningbo university (No. XKL11D2111 to Dr. Chuang Wang) and Student Research and Innovation Program (SRIP) of Ningbo University. This project also sponsored by K.C. Wong Magna funded at Ningbo University.

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The authors declare that no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People’s Republic of China

    Chuang Wang, Yang Lu, Peipei Lin, Tonghe Pan, Xin Zhao, Aiming Liu, Qinwen Wang & Wenhua Zhou

  2. Zhejiang Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People’s Republic of China

    Chuang Wang, Yang Lu, Peipei Lin, Tonghe Pan, Xin Zhao, Aiming Liu, Qinwen Wang & Wenhua Zhou

  3. Pingdu People’s Hospital, 112 Yangzhou Road, Qingdao, Shandong, 266700, People’s Republic of China

    Jianrui Zhang

  4. Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA

    Han-Ting Zhang

  5. Department of Behavioral Medicine & Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV, 26506-9137, USA

    Han-Ting Zhang

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  1. Chuang Wang
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Wang, C., Zhang, J., Lu, Y. et al. Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice. Metab Brain Dis 29, 673–682 (2014). https://doi.org/10.1007/s11011-014-9533-4

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