Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice
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- 作者：Junfang Zhang ; Jiejie Guo ; Xin Zhao ; Zhuoyou Chen ; Gang Wang ; Aiming Liu ; Qinwen Wang ; Wenhua Zhou ; Ying Xu ; Chuang Wang
- 关键词：Alzheimer's disease ; Phosphodiesterase-5 ; Sildenafil ; Neuroinflammation ; ¦Â-amyloid peptide ; cGMP-dependent protein kinase
- 刊名：Behavioural Brain Research
- 出版年：2013
- 出版时间：1 August, 2013
- 年：2013
- 卷：250
- 期：Complete
- 页码：230-237
- 全文大小：1941 K
文摘
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 ¦Â-amyloid peptide (A¦Â)-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 A¦Â1-40 and A¦Â1-42 levels 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 A¦Â levels.