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

Abstract

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. 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. Hcyb1 had a highly selective inhibition of PDE2A (IC50 =0.57±0.03μmol/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 24hours. 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 24hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT-22 cells for 24hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling.