title: Neuroprotection by sildenafil: neuronal networks potentiation in acute experimental stroke.
abstract: OBJECTIVE
  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.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Chen
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Wang
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Wu
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Yang
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D058851:GPI-Linked Proteins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D000070816:Nogo Receptor 1; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D000068677:Sildenafil Citrate; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009185:Myelin Proteins; D018696:Neuroprotective Agents; D000070816:Nogo Receptor 1; D010879:Piperazines; D011687:Purines; D011956:Receptors, Cell Surface; C486581:Rtn4r protein, rat; D013450:Sulfones; D016708:Synaptophysin; C569016:Syp protein, rat; D020932:Nerve Growth Factor; D000068677:Sildenafil Citrate; D052248:Nitric Oxide Synthase Type I; D020917:Receptor, trkA; D020813:Receptor, trkB
keywords: Neuronal network; Neuroprotection; Sildenafil; Stroke
references.citation: Anesthesiology. 2000 Jun;92(6):1702-12
references.pmid: 10839922
references.citation: Trends Pharmacol Sci. 2000 Dec;21(12):484-9
references.pmid: 11121838
references.citation: Stroke. 2012 Jul;43(7):1918-24
references.pmid: 22535263
references.citation: Stroke. 2010 Sep;41(9):2044-9
references.pmid: 20671245
references.citation: Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1976-81
references.pmid: 15591097
references.citation: Biochem J. 2001 Nov 15;360(Pt 1):199-208
references.pmid: 11696008
references.citation: Stroke. 2005 Apr;36(4):847-52
references.pmid: 15746452
references.citation: Neuropharmacology. 1996 May;35(5):541-7
references.pmid: 8887962
references.citation: J Neurosci. 2003 Nov 19;23(33):10681-90
references.pmid: 14627653
references.citation: J Neuroinflammation. 2010 Sep 14;7:55
references.pmid: 20836895
references.citation: J Neurocytol. 1996 Dec;25(12):821-8
references.pmid: 9023727
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G155-64
references.pmid: 17962360
references.citation: Brain Res. 2012 Feb 3;1436:168-77
references.pmid: 22221736
references.citation: Glia. 2012 May;60(6):948-64
references.pmid: 22431236
references.citation: Brain Res. 2006 Nov 6;1118(1):192-8
references.pmid: 16959227
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16329-34
references.pmid: 17911251
references.citation: Am J Respir Cell Mol Biol. 2012 Mar;46(3):323-30
references.pmid: 21997485
references.citation: Stroke. 2005 Oct;36(10):2251-7
references.pmid: 16141422
references.citation: Stroke. 2008 Apr;39(4):1300-6
references.pmid: 18309158
references.citation: Stroke. 2002 Nov;33(11):2675-80
references.pmid: 12411660
references.citation: Lancet. 2008 May 10;371(9624):1612-23
references.pmid: 18468545
references.citation: J Neurosci. 2009 Jun 24;29(25):8075-86
references.pmid: 19553447
references.citation: Stroke. 1992 Sep;23(9):1304-10; discussion 1310-1
references.pmid: 1519287
references.citation: J Cell Mol Med. 2005 Jan-Mar;9(1):59-71
references.pmid: 15784165
references.citation: Brain Res. 2003 Nov 28;992(1):53-9
references.pmid: 14604772
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1315-24
references.pmid: 20413734
references.citation: Nat Rev Neurosci. 2009 Dec;10(12):861-72
references.pmid: 19888284
references.citation: Neurosignals. 2002 Jul-Aug;11(4):175-90
references.pmid: 12393944
references.citation: J Cereb Blood Flow Metab. 2007 May;27(5):998-1009
references.pmid: 17033691
references.citation: Brain Res. 2009 Apr 10;1265:148-57
references.pmid: 19368809
references.citation: Brain Res. 2006 Oct 9;1114(1):212-20
references.pmid: 16928363
references.citation: J Neurosci. 2002 Nov 15;22(22):9868-76
references.pmid: 12427843
references.citation: Nat Cell Biol. 2011 Jun;13(6):660-7
references.pmid: 21572420
references.citation: Shock. 2003 Oct;20(4):369-74
references.pmid: 14501952
references.citation: Proc Natl Acad Sci U S A. 1988 Nov;85(22):8747-50
references.pmid: 2847175
references.citation: Trends Neurosci. 2007 Mar;30(3):119-25
references.pmid: 17267052
references.citation: Proc Natl Acad Sci U S A. 1982 Apr;79(8):2554-8
references.pmid: 6953413
references.citation: Front Mol Neurosci. 2011 Nov 03;4:39
references.pmid: 22065949
references.citation: Nat Rev Neurosci. 2003 May;4(5):399-415
references.pmid: 12728267
references.citation: Ann Neurol. 2007 Jul;62(1):49-58
references.pmid: 17557352
references.citation: J Neurochem. 1997 Oct;69(4):1438-48
references.pmid: 9326272
references.citation: Am J Physiol Heart Circ Physiol. 2011 Jun;300(6):H2272-9
references.pmid: 21398594
references.citation: Stroke. 2005 Sep;36(9):2000-5
references.pmid: 16040589
references.citation: Int Immunopharmacol. 2011 Apr;11(4):468-74
references.pmid: 21220057
references.citation: Brain Res. 2002 Jan 4;924(1):98-108
references.pmid: 11744000