title: Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice.
abstract: 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.
authors.affiliation: Department of Pharmacology of Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang Province, 315211, PR China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhang
authors.forename: Jiejie
authors.initials: J
authors.lastname: Guo
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Zhuoyou
authors.initials: Z
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Chuang
authors.initials: C
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000235:genetics; D011687:Purines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D013873:Thionucleotides
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; C508853:PSEN1 protein, human; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D053764:Presenilin-1; D011687:Purines; D012333:RNA, Messenger; D013450:Sulfones; D013873:Thionucleotides; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D000068677:Sildenafil Citrate; D006152:Cyclic GMP