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首页> 外文期刊>Brain research >Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system
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Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system

机译：磷酸二酯酶4抑制剂通过cAMP / CREB信号传导系统减轻醋酸脱氧皮质酮引起的高血压大鼠的认知功能障碍

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Phosphodiesterase-4 (PDE-4) inhibitors promote memory by blocking the degradation of cAMP. Existing evidence also shows that neuronal survival and plasticity are dependent on the phosphorylation of cAMP-response element-binding protein. In this regard, PDE-4 inhibitors have also been shown to reverse pharmacologically and genetically induced memory impairment in animal models. In the present study, the authors examined the effect of both rolipram and roflumilast (PDE-4 inhibitors) on the impairment of learning and memory observed in hypertensive rats. Deoxycorticosterone acetate (DOCA) salt hypertensive model was used to induce learning and memory deficits. The mRNA expression of different PDE-4 subtypes along with the protein levels of pCREB and BDNF in the hippocampus was quantified. Systolic blood pressure was significantly increased in DOCA salt hypertensive rats when compared to sham operated rats. This effect was reversed by clonidine, an alpha(2) receptor agonist, while PDE-4 inhibitors did not. PDE-4 inhibitors significantly improved the time-induced memory deficits in object recognition task (ORT). In DOCA salt hypertensive rats, the gene expression of PDE-4B and PDE-4D was significantly increased. Furthermore, both pCREB and BDNF showed decreased levels of expression in hypertensive rats in comparison to sham operated rats. Repeated administration of PDE-4 inhibitors significantly decreased both PDE-4B and PDE-4D with an increase in the expression of pCREB and BDNF in hypersensitive rats. Also, rolipram, roflumilast and roflumilast N-oxide showed a linear increase in the plasma and brain concentrations after ORT. Our present findings suggested that PDE-4 inhibitors ameliorate hypertension-induced learning impairment via cAMP/CREB signaling that regulates BDNF expression downstream in the rat hippocampus. (C) 2015 Elsevier B.V. All rights reserved.
机译：磷酸二酯酶4（PDE-4）抑制剂通过阻止cAMP的降解来促进记忆。现有证据还表明，神经元的存活和可塑性取决于cAMP反应元件结合蛋白的磷酸化。在这方面，PDE-4抑制剂还被证明可以逆转动物模型的药理和遗传诱导的记忆障碍。在本研究中，作者检查了咯利普兰和鲁氟司特（PDE-4抑制剂）对高血压大鼠学习和记忆障碍的影响。乙酸脱氧皮质酮（DOCA）盐高血压模型用于诱导学习和记忆障碍。量化不同PDE-4亚型的mRNA表达以及海马中pCREB和BDNF的蛋白水平。与假手术大鼠相比，DOCA盐高血压大鼠的收缩压显着升高。可乐定是一种α（2）受体激动剂，可逆转这种作用，而PDE-4抑制剂则不能。 PDE-4抑制剂显着改善了对象识别任务（ORT）中时间诱导的记忆缺陷。在DOCA盐高血压大鼠中，PDE-4B和PDE-4D的基因表达显着增加。此外，与假手术大鼠相比，pCREB和BDNF在高血压大鼠中均表现出降低的表达水平。重复施用PDE-4抑制剂可明显降低超敏大鼠的PDE-4B和PDE-4D，并增加pCREB和BDNF的表达。此外，ORT后，咯利普兰，鲁氟司特和鲁氟司特N-氧化物显示血浆和脑中浓度呈线性增加。我们目前的发现表明，PDE-4抑制剂通过调节大鼠海马下游BDNF表达的cAMP / CREB信号改善了高血压诱发的学习障碍。 （C）2015 Elsevier B.V.保留所有权利。

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