School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, 213164, China; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA.
Neuropharmacology. 2018 Dec;143:176-185. doi: 10.1016/j.neuropharm.2018.09.039. Epub 2018 Sep 27.
Phosphodiesterase 2 (PDE2) plays an important role in treatment of stress-related depression through regulation of antioxidant defense and neuroprotective mechanisms. However, the causal relationship between PDE2 and the prevalence of depression and anxiety upon exposure to oxidative stress has not been investigated. The present study examined whether the effects of PDE2 inhibition on oxidative stress were directly involved in reduced ROS by regulating NADPH subunits gp91phox oxidase. The results suggested that the PDE2 inhibitor Bay 60-7550 reversed oxidative stress-induced behavioral signature, i.e. depression and anxiety. Pretreatment with the oxidizing agent DTNB completely blocked, while the reducing agent DTT and the NADPH oxidase inhibitor apocynin potentiated the effects of Bay 60-7550 on behavioral abnormalities, demonstrating the relationship between PDE2 and oxidative stress. Consistently, an in vitro test revealed the positive correlation between ROS and PDE2 levels. Moreover, Bay 60-7550 decreased corticosterone-induced gp91phox expression, which is the source of ROS. The subsequent study suggested that Bay 60-7550 induced decrease in ROS and increase in cAMP/cGMP, pVASP, pCREB, and the neurotrophic factor BDNF levels, which were completely blocked by CRISPR/Cas9-mediated gp91phox overexpression and potentiated by gp91phox siRNA-based antioxidant strategies. The in vivo test in stressed mice further suggested that gp91phox overexpression completely blocked the antidepressant- and anxiolytic-like effects of Bay 60-7550, while gp91phox knockdown enhanced such effects. These results provide solid evidence that the antidepressant- and anxiolytic-like effects of Bay 60-7550 against stress are causally related to down-regulation of gp91phox and activation of the cAMP/cGMP-pVASP-CREB-BDNF signaling pathway.
磷酸二酯酶 2(PDE2)通过调节抗氧化防御和神经保护机制,在应激相关抑郁症的治疗中发挥着重要作用。然而,PDE2 与暴露于氧化应激时的抑郁和焦虑患病率之间的因果关系尚未得到研究。本研究旨在探讨 PDE2 抑制是否通过调节 NADPH 亚基 gp91phox 氧化酶直接参与减少 ROS,从而对氧化应激产生影响。结果表明,PDE2 抑制剂 Bay 60-7550 逆转了氧化应激诱导的行为特征,即抑郁和焦虑。氧化应激预处理剂 DTNB 完全阻断了 Bay 60-7550 的作用,而还原剂 DTT 和 NADPH 氧化酶抑制剂 apocynin 增强了 Bay 60-7550 对行为异常的作用,表明 PDE2 与氧化应激之间存在关系。同样,体外试验显示了 ROS 与 PDE2 水平之间的正相关关系。此外,Bay 60-7550 降低了皮质酮诱导的 gp91phox 表达,这是 ROS 的来源。随后的研究表明,Bay 60-7550 诱导 ROS 减少和 cAMP/cGMP、pVASP、pCREB 和神经营养因子 BDNF 水平增加,这些作用完全被 CRISPR/Cas9 介导的 gp91phox 过表达阻断,而被基于 gp91phox siRNA 的抗氧化策略增强。应激小鼠的体内试验进一步表明,gp91phox 过表达完全阻断了 Bay 60-7550 的抗抑郁和抗焦虑样作用,而 gp91phox 敲低增强了这种作用。这些结果为 Bay 60-7550 对压力的抗抑郁和抗焦虑样作用与 gp91phox 的下调和 cAMP/cGMP-pVASP-CREB-BDNF 信号通路的激活有关提供了确凿的证据。