PMID- 25064698 OWN - NLM STAT- MEDLINE DCOM- 20141217 LR - 20161125 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 261 DP - 2014 Nov TI - Yonkenafil: a novel phosphodiesterase type 5 inhibitor induces neuronal network potentiation by a cGMP-dependent Nogo-R axis in acute experimental stroke. PG - 267-77 LID - S0014-4886(14)00235-0 [pii] LID - 10.1016/j.expneurol.2014.07.007 [doi] AB - Yonkenafil is a novel phosphodiesterase type 5 (PDE5) inhibitor. Here we evaluated the effect of yonkenafil on ischemic injury and its possible mechanism of action. Male Sprague-Dawley rats underwent middle cerebral artery occlusion, followed by intraperitoneal or intravenous treatment with yonkenafil starting 2h later. Behavioral tests were carried out on day 1 or day 7 after reperfusion. Nissl staining, Fluoro-Jade B staining and electron microscopy studies were carried out 24h post-stroke, together with an analysis of infarct volume and severity of edema. Levels of cGMP-dependent Nogo-66 receptor (Nogo-R) pathway components, hsp70, apaf-1, caspase-3, caspase-9, synaptophysin, PSD-95/neuronal nitric oxide synthases (nNOS), brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) and nerve growth factor (NGF)/tropomyosin-related kinase A (TrkA) were also measured after 24h. Yonkenafil markedly inhibited infarction and edema, even when administration was delayed until 4h after stroke onset. This protection was associated with an improvement in neurological function and was sustained for 7d. Yonkenafil enlarged the range of penumbra, reduced ischemic cell apoptosis and the loss of neurons, and modulated the expression of proteins in the Nogo-R pathway. Moreover, yonkenafil protected the structure of synapses and increased the expression of synaptophysin, BDNF/TrkB and NGF/TrkA. In conclusion, yonkenafil protects neuronal networks from injury after stroke. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Chen, Xuemei AU - Chen X AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. FAU - Wang, Nannan AU - Wang N AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. FAU - Liu, Yueyang AU - Liu Y AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. FAU - Liu, Yinglu AU - Liu Y AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. FAU - Zhang, Tianyu AU - Zhang T AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. FAU - Zhu, Lei AU - Zhu L AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. FAU - Wang, Yongfeng AU - Wang Y AD - Zhuhai Oxforston PharmTech Co. Ltd., Tangjiawan, 519085 Zhuhai, PR China. FAU - Wu, Chunfu AU - Wu C AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. Electronic address: wucf@syphu.edu.cn. FAU - Yang, Jingyu AU - Yang J AD - Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. Electronic address: yangjingyu2006@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140723 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Fluoresceins) RN - 0 (GPI-Linked Proteins) RN - 0 (Myelin Proteins) RN - 0 (Neuroprotective Agents) RN - 0 (Nogo Receptor 1) RN - 0 (Phosphodiesterase 5 Inhibitors) RN - 0 (Plant Extracts) RN - 0 (Receptors, Cell Surface) RN - 0 (Rtn4r protein, rat) RN - 0 (fluoro jade) RN - EC 2.7.10.1 (Receptor, trkB) RN - H2D2X058MU (Cyclic GMP) SB - IM MH - Animals MH - Cyclic GMP/*metabolism MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Fluoresceins MH - GPI-Linked Proteins/metabolism MH - Infarction, Middle Cerebral Artery/complications/*drug therapy MH - Male MH - Myelin Proteins/*metabolism MH - Nervous System Diseases/drug therapy/etiology MH - Neuroprotective Agents/*therapeutic use MH - Nogo Receptor 1 MH - Phosphodiesterase 5 Inhibitors/*therapeutic use MH - Plant Extracts/therapeutic use MH - Psychomotor Performance/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, trkB/metabolism MH - Receptors, Cell Surface/*metabolism MH - Signal Transduction/*drug effects MH - Time Factors OTO - NOTNLM OT - Acute stroke OT - Focal ischemia OT - Neuroprotection OT - Rehabilitation OT - Reperfusion EDAT- 2014/07/30 06:00 MHDA- 2014/12/18 06:00 CRDT- 2014/07/28 06:00 PHST- 2014/03/28 00:00 [received] PHST- 2014/06/14 00:00 [revised] PHST- 2014/07/04 00:00 [accepted] PHST- 2014/07/28 06:00 [entrez] PHST- 2014/07/30 06:00 [pubmed] PHST- 2014/12/18 06:00 [medline] AID - S0014-4886(14)00235-0 [pii] AID - 10.1016/j.expneurol.2014.07.007 [doi] PST - ppublish SO - Exp Neurol. 2014 Nov;261:267-77. doi: 10.1016/j.expneurol.2014.07.007. Epub 2014 Jul 23.