Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress.
Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress.
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DOI：
10.1016/j.neurobiolaging.2014.08.028
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发表时间：
2015-02
影响因子：
4.2
通讯作者：
O'Donnell JM
中科院分区：
文献类型：
--
作者：
Xu Y;Pan J;Sun J;Ding L;Ruan L;Reed M;Yu X;Klabnik J;Lin D;Li J;Chen L;Zhang C;Zhang H;O'Donnell JM
慢性应激和神经元脆弱性最近被认为是认知障碍的因素。改变神经元脆弱性的一种方法是通过磷酸二酯酶2（PDE 2）的介导，磷酸二酯酶2是一种通过控制细胞内第二信使cGMP和在较小程度上cAMP来对认知过程发挥作用的酶。本研究探讨了PDE 2抑制剂Bay 60-7550对应激诱导的学习记忆功能障碍的影响，包括其对行为、形态和分子变化的影响。Bay 60-7550逆转了Morris水迷宫（MWM）中的应激诱导的认知障碍，新的物体识别和定位任务（ORT/奥尔特），通过7-NI（神经元型一氧化氮合酶（nNOS）的选择性抑制剂）、MK 801（谷氨酸受体（NMDAR）抑制剂）、myr-AIP（CaMKII抑制剂）和KT 5823（PKG抑制剂）治疗预防了这种效应。Bay 60-7550还改善了海马CA 1区应激诱导的结构重塑，导致树突分支、长度和棘密度增加。然而，在7-NI、MK 801、myr-AIP或KT 5823的存在下，未观察到Bay 60-7550引发的神经可塑性。PDE 2抑制降低了应激诱导的ERK活化并减弱了应激诱导的转录因子（例如，Elk-1、TORC 1和pCREB）和可塑性相关蛋白（例如，Egr-1和BDNF）。用NMDA、CaMK II、nNOS、PKG（或PKA）的抑制剂预处理阻断Bay 60-7550对cGMP或cAMP信号传导的作用。这些发现表明，PDE 2抑制对应激诱导的记忆障碍的影响可能是通过调节神经可塑性相关的NMDAR-CaMKII-cGMP/cAMP信号传导介导的。
Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphological and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze (MWM), novel object recognition and location tasks (ORT/OLT), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase (nNOS); MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a PKG inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP or KT5823. PDE2 inhibition reduced stress-induced ERK activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and pCREB) and plasticity-related proteins (e.g, Egr-1 and BDNF). Pre-treatment with inhibitors of NMDA, CaMKII, nNOS, PKG (or PKA), blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related, NMDAR-CaMKII-cGMP/cAMP signaling.
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影响因子：
2.7
作者：
de Lima, MNM;Laranja, DC;Schröder, N
通讯作者：
Schröder, N
DOI：
10.1523/jneurosci.5236-10.2011
发表时间：
2011-01-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li YF;Cheng YF;Huang Y;Conti M;Wilson SP;O'Donnell JM;Zhang HT
通讯作者：
Zhang HT
DOI：
10.1073/pnas.0908563106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Hains, Avis Brennan;Vu, Mai Anh T.;Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
DOI：
10.1098/rstb.2001.0947
发表时间：
2001-09-29
影响因子：
6.3
作者：
Clayton, NS;Griffiths, DP;Dickinson, A
通讯作者：
Dickinson, A
影响因子：
3.7
作者：
Cho T;Ryu JK;Taghibiglou C;Ge Y;Chan AW;Liu L;Lu J;McLarnon JG;Wang YT
通讯作者：
Wang YT