Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice
Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice
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磷酸二酯酶 5 抑制剂西地那非可预防 APP/PS1 转基因小鼠的神经炎症、降低 β-淀粉样蛋白水平并改善认知能力
DOI：
10.1016/j.bbr.2013.05.017
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发表时间：
2013-08
影响因子：
2.7
通讯作者：
Wang, Chuang
中科院分区：
文献类型：
--
作者：
Wang, Qinwen;Zhou, Wenhua;Xu, Ying;Wang, Chuang
记忆缺陷是阿尔茨海默病（AD）的标志物，其与环GMP（cGMP）信号传导功能障碍和持续的炎症过程高度相关。磷酸二酯酶-5（PDE 5）抑制剂可防止cGMP的分解，目前被研究为认知增强的可能靶点。然而，在APP/PS1转基因（Tg APP/PS1）小鼠中，抑制PDE 5是否逆转β-淀粉样肽（Aβ）诱导的神经炎症仍然是未知的。本研究评估了15月龄Tg APP/PS1小鼠和年龄匹配的野生型（WT）小鼠的认知行为、炎症介质和cGMP/PKG/pCREB信号传导，这些小鼠接受了PDE 5抑制剂西地那非和cGMP依赖性蛋白激酶Rp-8-Br-PET-cGMPS抑制剂治疗。与WT小鼠相比，Tg APP/PS1小鼠的特征在于认知能力受损、神经炎症反应和cGMP信号转导下调。西地那非可逆转这些记忆缺陷和cGMP/PKG/pCREB信号传导功能障碍;它还可降低海马中可溶性Aβ1- 40和Aβ1- 42的水平。海马内输注Rp-8-Br-PET-cGMPS可预防西地那非的这些作用。这些结果提示西地那非可通过调节PKG/pCREB信号通路、抗炎反应和降低Aβ水平来恢复Tg APP/PS1小鼠的认知功能障碍。
Memory deficit is a marker of Alzheimer's disease (AD) that has been highly associated with the dysfunction of cyclic GMP (cGMP) signaling and an ongoing inflammatory process. Phosphodiesterase-5 (PDE5) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement. However, it is still unknown whether inhibition of PDE5 reversed β-amyloid peptide (Aβ)-induced neuroinflammation in APP/PS1 transgenic (Tg APP/PS1) mice. The present study evaluated the cognitive behaviors, inflammatory mediators, and cGMP/PKG/pCREB signaling in 15-month-old Tg APP/PS1 mice and age-matched wild-type (WT) mice that were treated with PDE5 inhibitor sildenafil and the inhibitor of cGMP-dependent protein kinase Rp-8-Br-PET-cGMPS. In comparison with WT mice, Tg APP/PS1 mice were characterized by impaired cognitive ability, neuroinflammatory response, and down-regulated cGMP signaling. Sildenafil reversed these memory deficits and cGMP/PKG/pCREB signaling dysfunction; it also reduced both the soluble Aβ1–40and Aβ1–42levels in the hippocampus. These effects of sildenafil were prevented by intra-hippocampal infusion of the Rp-8-Br-PET-cGMPS. These results suggest that sildenafil could restore cognitive deficits in Tg APP/PS1 mice by the regulation of PKG/pCREB signaling, anti-inflammatory response and reduction of Aβ levels.
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影响因子：
3.1
作者：
A. Vehmas;D. Borchelt;D. Price;D. McCarthy;M. Wills-Karp;M. Peper;J. Luyinbazi;L. T. Siew;J. Troncoso
通讯作者：
A. Vehmas;D. Borchelt;D. Price;D. McCarthy;M. Wills-Karp;M. Peper;J. Luyinbazi;L. T. Siew;J. Troncoso
影响因子：
4.7
作者：
Xin Wang;P. Robinson
通讯作者：
Xin Wang;P. Robinson
DOI：
--
发表时间：
2005
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Qinwen Wang;Jinqun Wu;M. Rowan;R. Anwyl
通讯作者：
Qinwen Wang;Jinqun Wu;M. Rowan;R. Anwyl
影响因子：
3.3
作者：
Zhang, Rongzhen;Miller, Robert G.;Madison, Catherine;Jin, Xia;Honrada, Ronald;Harris, Will;Katz, Jonathan;Forshew, Dallas A.;McGrath, Michael S.
通讯作者：
McGrath, Michael S.
DOI：
10.1523/jneurosci.1729-12.2012
发表时间：
2012-10-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cameron B;Tse W;Lamb R;Li X;Lamb BT;Landreth GE
通讯作者：
Landreth GE