Inhibition of phosphodiesterase 2 reverses NADPH oxidase mediated depression-like behaviors  

出　　处：《中国药理学通报》2015年第B11期268-269,共2页Chinese Pharmacological Bulletin

摘　　要：Depression is a recurring and potentially lifethreatening disorderthat is major cause of morbidity and mor-tality. Stressful eventscan precipitate factors in the onset of major depressionand stress paradigms have long been used to modeldepressive status. The stress hormone glucocorticoid generates superoxide via increase in NADPH oxi- dase, which results inover-stimulation of phosphodiesterase 2 （PDE2） activity during stress. The present study in- vestigated whether PDE2 overexpression led to dysfunction of cyclic adenosine monophosphate （cAMP）/and cyclic guanosine monophosphate （cGMP） signaling that rapidly affects emotional function. The results suggested thatinhi- bition of PDE2by Bay 60 - 7550 and lenti-PDE2-miRNA reversedstress-induced depression-like behaviors. Consid- ering that memory improvement is the critical determinant of functional outcome in treatment of major depression, the cognitive performance was also studied. PDE2 inhibition was shown to improve the cognition in the Morris water maze and novel object recognition tests. Pretreatment with the oxidizing agent DTNB prevented, while the reducing agent DTT and NADPH oxidase inhibitor apocynin potentiated, the effects of Bay 60 - 7550 on behaviors in depres- sion and cognition, indicating the role of PDE2 in the oxidative stress-induced depression associated cognitive defi- cits. Consistently, the increases in dendritic branching and length of hippocampal neurons after inhibition of PDE2 were suppressed by DTNB; whereas the potentiation was observed by treatment with DTT or apocynin. The subse- quent in vitrostudy suggested that oxidative stress-induced ROS expression was positively related to PDE2 levels, which was consistent with the in vivo data. PDE2 inhibitor Bay 60 - 7550 and silencing PDE2 by lenti-PDE2-miR- NA decreased stress hormone corticosterone-induced increases in NADPH oxidase subunits, such as gp91 phox, in the hippocampal cells. The fact that gp91 phox knockdown potentiated the effect of PDE2 inhibition on depression and

关 键 词：NADPH氧化酶 氧化酶抑制剂 磷酸二酯酶 认知行为 抑郁样 氧化剂 PHOSPHODIESTERASE CAMP/CGMP 

分 类 号：R495.5[医药卫生—康复医学] R742.505[医药卫生—临床医学]