Depressive-and anxiety-like behaviors involve an oxidative damage in the brain of stressed mice:protective effects of phosphodiesterase 2 inhibitor

Cyclic GMP-PKG signaling plays a crucial role in neuropsychiatric disorders such as depression/anxiety that is often characterized with oxidative stress and neuronal cell apoptosis.Phosphodiesterase 2(PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala,which may be important in treatment of depression and anxiety through regulation of oxidative stress and apoptosis.To address the possible effects of PDE2 inhibitor on depressive-and anxiety-like behaviors and on neurons of hippocampus and amygdala,different doses of Bay 60-7550(1 and 3 mg·kg-1,ip) were administered in chronically stressed mice.The data suggested that higher dose of Bay 60-7550 reversed chronic stress-induced depressive-and anxiety-like behaviors,which may be due to Bay 60-7550′s ability to alleviate oxidative stress and to reverse the adverse effect of stress on cGMP/PKG signaling,as assessed by Cu/Zn superoxide dismutase(SOD) levels,an enzyme involved in superoxide detoxfication,and phosphorylation of VASPser239,an indicator of PKG signaling in the hippocampus and amygdala.Interestingly,Bay 60-7550 regulates the SOD expression differentially in hippocampus and amygdala,which were increased in the hippocampus while decreased in the amygdala.Furthermore,Bay 60-7550 was found to decrease the expression of apoptosis related proteins in these two brain regions,such as Bax and caspase 3,which were induced by chronic stress.However,the expression of B cell lymphoma protein-2(Bcl-2) was increased after treatment with Bay 60-7550.These data strongly suggest that PDE2 produces antidepressant-and anxiolytic-like effects primarily through SOD-cGMP/PKG-antiapoptosis signaling,which indicates a potential candidate for treatment of neuropsychiatric disorders.