title: Yonkenafil: a novel phosphodiesterase type 5 inhibitor induces neuronal network potentiation by a cGMP-dependent Nogo-R axis in acute experimental stroke.
abstract: 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.
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors: Xuemei
authors: X
authors: Chen
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors: Nannan
authors: N
authors: Wang
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors: Yueyang
authors: Y
authors: Liu
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors: Yinglu
authors: Y
authors: Liu
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors: Tianyu
authors: T
authors: Zhang
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors: Lei
authors: L
authors: Zhu
authors: Zhuhai Oxforston PharmTech Co. Ltd., Tangjiawan, 519085 Zhuhai, PR China.
authors: Yongfeng
authors: Y
authors: Wang
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. Electronic address: wucf@syphu.edu.cn.
authors: Chunfu
authors: C
authors: Wu
authors: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. Electronic address: yangjingyu2006@gmail.com.
authors: Jingyu
authors: J
authors: Yang
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D058851:GPI-Linked Proteins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy*; D008297:Male; D009185:Myelin Proteins / Q000378:metabolism*; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D000070816:Nogo Receptor 1; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010936:Plant Extracts / Q000627:therapeutic use; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D005452:Fluoresceins; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D018696:Neuroprotective Agents; D000070816:Nogo Receptor 1; D058986:Phosphodiesterase 5 Inhibitors; D010936:Plant Extracts; D011956:Receptors, Cell Surface; C486581:Rtn4r protein, rat; C435731:fluoro jade; D020813:Receptor, trkB; D006152:Cyclic GMP
keywords: Acute stroke; Focal ischemia; Neuroprotection; Rehabilitation; Reperfusion