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

CNS Neurosci Ther. 2018 Oct;24(10):889-896. doi: 10.1111/cns.12864. Epub 2018 May 2.


Background: Major 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.

Methods: We 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 1 mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice.

Results: C36D 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.

Conclusion: Our 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.

Keywords: BDNF; CREB; C36D; PDE9 inhibitor; depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CREB-Binding Protein / metabolism
  • Cell Line, Transformed
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Corticosterone / toxicity*
  • Cyclic GMP / metabolism*
  • Depression / drug therapy*
  • Depression / psychology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hindlimb Suspension / psychology
  • Locomotion / drug effects
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred ICR
  • Neurotoxicity Syndromes / drug therapy*
  • Neurotoxicity Syndromes / etiology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Recognition, Psychology / drug effects
  • Restraint, Physical / adverse effects
  • Signal Transduction / drug effects*
  • Swimming / psychology


  • Phosphodiesterase Inhibitors
  • CREB-Binding Protein
  • Cyclic GMP
  • Corticosterone