The neuroprotective and antidepressant-like effects of Hcyb1, a novel selective PDE2 inhibitor

CNS Neurosci Ther. 2018 Jul;24(7):652-660. doi: 10.1111/cns.12863. Epub 2018 Apr 27.

Abstract

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 PDE2 inhibitor, in HT-22 cells and antidepressant-like effects in mouse models of depression.

Methods: Hcyb1 was synthesized and its selectivity upon PDE2 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 PDE2A (IC50 = 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 PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling.

Keywords: Hcyb1; antidepressant; cell viability; cyclic nucleotide; forced swim test; phosphodiesterase 2(PDE2) inhibitor; tail suspension test.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism
  • Cell Line, Transformed
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Depression / drug therapy*
  • Disease Models, Animal
  • Guanine / analogs & derivatives*
  • Guanine / chemistry
  • Guanine / pharmacology
  • Guanine / therapeutic use
  • Hindlimb Suspension / methods
  • Inhibitory Concentration 50
  • Locomotion / drug effects
  • Male
  • Mice
  • Mice, Inbred ICR
  • N-Methylaspartate / toxicity
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Naphthalenes / therapeutic use*
  • Neurons / drug effects*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Swimming

Substances

  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Naphthalenes
  • Neuroprotective Agents
  • PDE2 inhibitor hcyb1
  • Phosphodiesterase Inhibitors
  • Guanine
  • N-Methylaspartate
  • Cyclic AMP
  • CREB-Binding Protein
  • Cyclic GMP