title: A novel phosphodiesterase-5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model.
abstract: In Alzheimer's disease (AD), activated microglia invade and surround β-amyloid plaques, possibly contributing to the aggregation of amyloid β (Aβ), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PS1 transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (sild) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of Aβ plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PS1 mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX(+) cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China.
authors.forename: Jing-yu
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China.
authors.forename: Ying-xu
authors.initials: YX
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China.
authors.forename: Feng-rong
authors.initials: FR
authors.lastname: Miao
authors.affiliation: Zhuhai Oxforston PharmTech Co. Ltd, Tangjiawan, 519085 Zhuhai, China.
authors.forename: Yong-feng
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China; Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address: hxue@ust.hk.
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Box 31, 103 Wenhua Road, 110016 Shenyang, China. Electronic address: wucf@syphu.edu.cn.
authors.forename: Chun-fu
authors.initials: CF
authors.lastname: Wu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D005911:Gliosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D058986:Phosphodiesterase 5 Inhibitors
keywords: Cognitive; Microglia; Neurogenesis; Yonkenafil; β-amyloid