Phosphodiesterase-2 inhibitor reverses post-traumatic stress induced fear memory deficits and behavioral changes via cAMP/cGMP pathway
Phosphodiesterase-2 inhibitor reverses post-traumatic stress induced fear memory deficits and behavioral changes via cAMP/cGMP pathway
复制标题
DOI：
10.1016/j.ejphar.2020.173768
复制
发表时间：
2021-01-15
影响因子：
5
通讯作者：
Pan, Jianchun
中科院分区：
文献类型：
--
作者：
Chen, Ling;Liu, Kaiping;Pan, Jianchun
磷酸二酯酶2是磷酸二酯酶（PDE）家族中调节环核苷酸（即cAMP和cGMP）浓度的成员之一。本研究确定了PDE 2抑制是否可以挽救创伤后应激障碍（PTSD）样症状。使小鼠经受单次延长应激（SPS）并用选择性PDE 2抑制剂Bay 60-7550（0.3、1或3 mg/kg，腹膜内）处理。采用强迫游泳、蔗糖偏好实验、旷场实验、高架十字迷宫实验和情境恐惧实验等行为学实验，观察Bay 60-7550对SPS诱导的抑郁样和焦虑样行为及恐惧记忆障碍的影响。结果表明，Bay 60-7550逆转了SPS诱导的抑郁和焦虑样行为以及恐惧记忆缺陷。此外，Bay 60-7550防止SPS诱导的肾上腺指数、突触蛋白突触素和PSD 95表达、海马和杏仁核中PKA、PKG、pCREB和BDNF水平的变化。PKG抑制剂KT 5823可完全阻止这些作用。PKA抑制剂H89也抑制Bay 60-7550诱导的pCREB和BDNF表达，但仅部分抑制PSD 95表达。这些发现表明，Bay 60-7550通过激活cGMP或cAMP相关的神经保护分子，如突触蛋白、pCREB和BDNF，保护小鼠免受PTSD样应激诱导的创伤性损伤。
Phosphodiesterase 2 is one of the phosphodiesterase (PDEs) family members that regulate cyclic nucleotide (namely cAMP and cGMP) concentrations. The present study determined whether PDE2 inhibition could rescue post-traumatic stress disorder (PTSD)-like symptoms. Mice were subjected to single prolonged stress (SPS) and treated with selective PDE2 inhibitor Bay 60-7550 (0.3, 1, or 3 mg/kg, i.p.). The behavioral tests such as forced swimming, sucrose preference test, open field, elevated plus maze, and contextual fear paradigm were conducted to determine the effects of Bay 60-7550 on SPS-induced depression- and anxiety-like behavior and fear memory deficits. The results suggested that Bay 60-7550 reversed SPS-induced depression- and anxiety-like behavior and fear memory deficits. Moreover, Bay 60-7550 prevented SPS-induced changes in the adrenal gland index, synaptic proteins synaptophysin and PSD95 expression, PKA, PKG, pCREB, and BDNF levels in the hippocampus and amygdala. These effects were completely prevented by PKG inhibitor KT5823. While PKA inhibitor H89 also prevented Bay 60-7550-induced pCREB and BDNF expression, but only partially prevented the effects on PSD95 expression in the hippocampus. These findings suggest that Bay 60-7550 protects mice against PTSD-like stress induced traumatic injury by activation of cGMP- or cAMP-related neuroprotective molecules, such as synaptic proteins, pCREB and BDNF.