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: Xuemei Chen, Nannan Wang, Yueyang Liu, Yinglu Liu, Tianyu Zhang, Lei Zhu, Yongfeng Wang, Chunfu Wu, Jingyu Yang
• Journal: Experimental neurology (Exp Neurol) Vol. 261 Pg. 267-77 (Nov 2014) ISSN: 1090-2430 [Electronic] United States
• PMID: 25064698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Fluoresceins
• GPI-Linked Proteins
• Myelin Proteins
• Neuroprotective Agents
• Nogo Receptor 1
• Phosphodiesterase 5 Inhibitors
• Plant Extracts
• Receptors, Cell Surface
• Rtn4r protein, rat
• fluoro jade
• Receptor, trkB
• Cyclic GMP

Topics

• Animals
• Cyclic GMP (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fluoresceins
• GPI-Linked Proteins (metabolism)
• Infarction, Middle Cerebral Artery (complications, drug therapy)
• Male
• Myelin Proteins (metabolism)
• Nervous System Diseases (drug therapy, etiology)
• Neuroprotective Agents (therapeutic use)
• Nogo Receptor 1
• Phosphodiesterase 5 Inhibitors (therapeutic use)
• Plant Extracts (therapeutic use)
• Psychomotor Performance (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptor, trkB (metabolism)
• Receptors, Cell Surface (metabolism)
• Signal Transduction (drug effects)
• Time Factors