A novel PDE9 inhibitor WYQ-C36D ameliorates corticosterone-induced neurotoxicity and depression-like behaviors by cGMP-CREB-related signaling

作者:Huang, Xian-Feng; Jiang, Wen-Tao; Liu, Li; Song, Fang-Chen; Zhu, Xia; Shi, Gui-Lan; Ding, Shu-Ming; Ke, Heng-Ming; Wang, Wei; O'Donnell, James M.; Zhang, Han-Ting; Luo, Hai-Bin; Wan, Yi-Qian; Song, Guo-Qiang*; Xu, Ying*
来源:CNS Neuroscience & Therapeutics, 2018, 24(10): 889-896.
DOI:10.1111/cns.12864

摘要

BackgroundMajor depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. @@@ MethodsWe examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice. @@@ ResultsC36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp-8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. @@@ ConclusionOur results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.