cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats.
cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats.
复制标题
cAMP/PKA/CREB/GLT1 信号传导参与磷酸二酯酶 4D 抑制剂 (GEBR-7b) 对大鼠的抗抑郁样作用
DOI：
10.2147/ndt.s90960
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发表时间：
2016
影响因子：
3.2
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Liu X;Guo H;Sayed MD;Lu Y;Yang T;Zhou D;Chen Z;Wang H;Wang C;Xu J
目的GEBR-7 b是一种潜在的磷酸二酯酶4D抑制剂，在啮齿类动物中具有增强记忆的作用。然而，目前尚不清楚GEBR-7 b是否在大鼠中也具有抗抑郁样作用。在此，我们研究了GEBR-7 b在慢性不可预测应激（CUS）诱导的抑郁症大鼠模型中减弱抑郁样行为的潜力。接下来，我们还研究了GEBR-7 b在抑郁症大鼠模型中产生的环磷酸腺苷（cAMP）、蛋白激酶A（PKA）催化亚基（PKAca）、cAMP反应元件结合（CREB）和谷氨酸转运体1（GLT 1）水平的变化。方法采用强迫游泳实验（FST）测定大鼠不动时间，观察GEBR-7 b对CUS诱导的抑郁样行为的影响。通过酶联免疫吸附试验检测海马cAMP水平，而大鼠海马中的PKAca、CREB磷酸化（pCREB）、CREB和GLT 1进行Western印迹分析。结果CUS暴露可引起大鼠抑郁样行为，表现为FST不动时间增加。CUS诱导的抑郁样行为伴随着海马GLT显著增加，cAMP、PKAca、pCREB活性显著降低。然而，重复给予GEBR-7 b可显著逆转海马神经元诱导的抑郁样行为和cAMP/PKA/CREB/GLT 1信号通路的变化。在旷场试验中未观察到自发活动的改变。结论GEBR-7 b可逆转CUS诱导的大鼠抑郁样行为，其机制可能与调节海马cAMP、PKAca、pCREB和GLT 1水平有关，提示GEBR-7 b对CUS诱导的大鼠抑郁样行为具有神经保护作用。
Objectives GEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression. Methods Effects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis. Results CUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test. Conclusion These findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS.