Open AccessThe neuroprotective and antidepressant‐like effects of Hcyb1, a novel selective PDE2 inhibitor
Author(s) -
Liu Li,
Zheng Jing,
Huang XianFeng,
Zhu Xia,
Ding ShuMing,
Ke HengMing,
O'Donnell James M.,
Zhang HanTing,
Song GuoQiang,
Xu Ying
Publication year - 2018
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12863
Subject(s) - tail suspension test , cyclic adenosine monophosphate , cyclic guanosine monophosphate , creb , neuroprotection , viability assay , pharmacology , phosphodiesterase , chemistry , adenosine , endocrinology , antidepressant , medicine , biochemistry , biology , behavioural despair test , in vitro , enzyme , receptor , hippocampus , transcription factor , nitric oxide , gene
Summary Aims Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate ( cAMP ) and/or cyclic guanosine monophosphate ( cGMP ) signaling by phosphodiesterase ( PDE ) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE 2 inhibitor, in HT ‐22 cells and antidepressant‐like effects in mouse models of depression. Methods Hcyb1 was synthesized and its selectivity upon PDE 2 was tested. Moreover, HT ‐22 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP / cGMP signaling by neurochemical, enzyme‐linked immunosorbent, and immunoblot assays in vitro. The antidepressant‐like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice. Results Hcyb1 had a highly selective inhibition of PDE 2A ( IC 50 = 0.57 ± 0.03 μmol/L) and over 250‐fold selectivity against other recombinant PDE family members. Hcyb1 at concentrations of 10 −10 and 10 −9 mol/L significantly increased cell viability after treatment for 24 hours. At concentrations of 10 −9 ~10 −7 mol/L, Hcyb1 also increased cGMP levels by 1.7~2.3 folds after 10‐minute treatment. Furthermore, Hcyb1 at the concentrations of 10 −9 mol/L increased both cGMP and cAMP levels 24 hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT ‐22 cells for 24 hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2 mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. Conclusion These results suggest that the novel PDE 2 inhibitor Hcyb1 produced neuroprotective and antidepressant‐like effects most likely mediated by cAMP / cGMP ‐ CREB ‐ BDNF signaling.