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

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 ± 0.03 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.

These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling.