title: Oxytocin is involved in the proconvulsant effects of Sildenafil: Possible role of CREB.
abstract: Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole-induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mahsima
authors.initials: M
authors.lastname: Khoshneviszadeh
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Center of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada. Electronic address: rahimian78@gmail.com.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahimian
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Center of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada. Electronic address: gfakhfouri@yahoo.com.
authors.forename: Gohar
authors.initials: G
authors.lastname: Fakhfouri
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Borna
authors.initials: B
authors.lastname: Payandemehr
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shahram
authors.initials: S
authors.lastname: Ejtemaei Mehr
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpour@yahoo.com.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D010121:Oxytocin / Q000378:metabolism*; D010433:Pentylenetetrazole; D058986:Phosphodiesterase 5 Inhibitors / Q000633:toxicity*; D010766:Phosphorylation; D018045:Receptors, Oxytocin / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate / Q000633:toxicity*; D013997:Time Factors; D014668:Vasotocin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D006727:Hormone Antagonists; C576074:OXTR protein, mouse; D058986:Phosphodiesterase 5 Inhibitors; D018045:Receptors, Oxytocin; C047046:atosiban; D010121:Oxytocin; D000068677:Sildenafil Citrate; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D014668:Vasotocin; D010433:Pentylenetetrazole
keywords: CREB phosphorylation; Mice; Oxytocin; Seizure; Sildenafil