Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice

• Published in: Behavioural brain research 2013-08, Vol.250, p.230-237
• Main Authors: Zhang, Junfang, Guo, Jiejie, Zhao, Xin, Chen, Zhuoyou, Wang, Gang, Liu, Aiming, Wang, Qinwen, Zhou, Wenhua, Xu, Ying, Wang, Chuang
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Analysis of Variance; Animals; Behavioral psychophysiology; Biological and medical sciences; cGMP-dependent protein kinase; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognition Disorders - genetics; Cyclic GMP - analogs & derivatives; Cyclic GMP - therapeutic use; Cytokines - genetics; Cytokines - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis - complications; Encephalitis - genetics; Encephalitis - prevention & control; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Neuroinflammation; Neurology; Organic mental disorders. Neuropsychology; Phosphodiesterase 5 Inhibitors - therapeutic use; Phosphodiesterase-5; Piperazines - therapeutic use; Presenilin-1 - genetics; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopathology. Psychiatry; Purines - therapeutic use; Recognition (Psychology) - drug effects; Recognition (Psychology) - physiology; RNA, Messenger - metabolism; Sildenafil; Sildenafil Citrate; Sulfones - therapeutic use; Thionucleotides; β-amyloid peptide
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2013.05.017

•Phosphodiesterase-5 (PDE5) inhibitor sildenafil ameliorates cognitive performance.•Sildenafil significantly rescues CREB phosphorylation and lowers Aβ levels.•Sildenafil may be as a potential therapeutic agent in long-term AD therapy. 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 Aβ1–40 and Aβ1–42 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 Aβ levels.