Neuroprotection by sildenafil: neuronal networks potentiation in acute experimental stroke.

Abstract

AIMS:

Sildenafil, a phosphodiesterase type 5 inhibitor, has been found to produce functional recovery in ischemic rats by increasing the cGMP level and triggering neurogenesis. The aim of this study was to investigate further sildenafil mechanisms.

METHODS:

Male Sprague-Dawley rats underwent middle cerebral artery occlusion and reperfusion, followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later. Behavioral tests were performed on day 1 or day 7 after reperfusion, while cerebral infarction, edema, Nissl staining, Fluoro-Jade B staining, and electron microscopy studies were carried out 24 h poststroke. The cGMP-dependent Nogo-66 receptor (Nogo-R) pathway, 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 measured.

RESULTS:

Sildenafil enhanced neurological recovery and inhibited infarction, even following delayed administration 4 h after stroke onset. Furthermore, sildenafil reduced the loss of neurons and modulated the expressions of the cGMP-dependent Nogo-R pathway. Moreover, sildenafil protected the structure of synapses and mediated the expressions of synaptophysin, PSD-95/nNOS, BDNF/TrkB, and NGF/TrkA.

CONCLUSIONS:

Sildenafil produces significant neuroprotective effects on injured neurons in acute stroke, and these are mediated by the cGMP-dependent Nogo-R pathway, NGF/TrkA, and BDNF/TrkB.

• Authors: Xue-Mei Chen, Nan-Nan Wang, Tian-Yu Zhang, Fang Wang, Chun-Fu Wu, Jing-Yu Yang
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 20 Issue 1 Pg. 40-9 (Jan 2014) ISSN: 1755-5949 [Electronic] England
• PMID: 24034153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• Brain-Derived Neurotrophic Factor
• Disks Large Homolog 4 Protein
• Dlg4 protein, rat
• GPI-Linked Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Myelin Proteins
• Neuroprotective Agents
• Nogo Receptor 1
• Piperazines
• Purines
• Receptors, Cell Surface
• Rtn4r protein, rat
• Sulfones
• Synaptophysin
• Syp protein, rat
• Nerve Growth Factor
• Sildenafil Citrate
• Nitric Oxide Synthase Type I
• Receptor, trkA
• Receptor, trkB

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Survival (drug effects)
• Disks Large Homolog 4 Protein
• GPI-Linked Proteins (metabolism)
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Membrane Proteins (metabolism)
• Myelin Proteins (metabolism)
• Nerve Growth Factor (metabolism)
• Nerve Net (drug effects, physiology)
• Neurons (drug effects, physiology, ultrastructure)
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Nitric Oxide Synthase Type I (metabolism)
• Nogo Receptor 1
• Piperazines (administration & dosage, therapeutic use)
• Purines (administration & dosage, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, trkA (metabolism)
• Receptor, trkB (metabolism)
• Receptors, Cell Surface (metabolism)
• Recovery of Function (drug effects)
• Reperfusion Injury (drug therapy, pathology)
• Sildenafil Citrate
• Stroke (drug therapy, pathology)
• Sulfones (administration & dosage, therapeutic use)
• Synapses (drug effects, ultrastructure)
• Synaptophysin (metabolism)