1947 DOWNREGULATION OF NGF EXPRESSION IN THE BLADDER BY ANTISENSE OLIGOUCLEOTIDES AS NEW TREATMENT OF OVERACTIVE BLADDER (2013)

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Non-neurogenic Voiding Dysfunction1 Apr 20131947 DOWNREGULATION OF NGF EXPRESSION IN THE BLADDER BY ANTISENSE OLIGOUCLEOTIDES AS NEW TREATMENT OF OVERACTIVE BLADDER Naoki Kawamorita, Mahendra Kashyap, Vikas Tyagi, Yoshio Sugino, Michael Chancellor, Naoki Yoshimura, and Pradeep Tyagi Naoki KawamoritaNaoki Kawamorita Pittsburgh, PA More articles by this author , Mahendra KashyapMahendra Kashyap Pittsburgh, PA More articles by this author , Vikas TyagiVikas Tyagi Pittsburgh, PA More articles by this author , Yoshio SuginoYoshio Sugino Pittsburgh, PA More articles by this author , Michael ChancellorMichael Chancellor Royal Oak, MI More articles by this author , Naoki YoshimuraNaoki Yoshimura Pittsburgh, PA More articles by this author , and Pradeep TyagiPradeep Tyagi Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2366AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Overexpression of NGF in the urothelium has been shown to play a role in symptoms of OAB by mediating functional changes of bladder afferents. We studied whether the blockade of NGF overexpression in the urothelium by a sequence-specific gene-silencing mechanism suppresses acetic acid (AA) induced bladder overactivity. METHODS Female Sprague-Dawley rats anaesthetized with isoflurane were instilled with 0.5mL of either saline, scrambled or TYE563-labelled antisense oligonucleotide (ODN) targeting NGF (12μM) alone or complexed with cationic liposomes for 30min. 24h later, the efficacy of antisense treatment was assessed by saline and AA infused cystometry under urethane anesthesia (1.2g/kg, s.c.). The expression levels and the bladder distribution of NGF after treatment were quantified by immunofluorescence staining and ELISA. RESULTS Liposomes were necessary for bladder uptake of ODN as revealed by absence of bright red fluorescence of TYE 563 in rat bladder instilled with ODN alone. 24h after instillation, the baseline CMG under saline infusion was indistinct with mean intercontraction interval (ICI) of 348.4±55.0 sec and 390.8±120.7 sec in the sham and antisense treated groups, respectively. In sham rats instilled with vehicle, AA infusion reduced the ICI to 33.2±4.0% of baseline values, compared to 75.8±3.4% of baseline values (n=6) in rats instilled with liposomal antisense ODN. AA induced elevation of NGF in the urothelium and detrusor of sham rat was also reduced by antisense treatment as revealed by ELISA (panel A&B) and reduced density of NGF immunoreactivity in the urothelium. Expression of NGF mRNA in rats treated with antisense ODN was also downregulated to 50% of control rats (panel C). CONCLUSIONS Our findings demonstrate that bladder overactivity induced by bladder irritation is associated with overexpression of NGF in the urothelium and that pretreatment with intravesical antisense suppresses expression of urothelial NGF and AA-induced bladder overactivity. Thus, local suppression of NGF in the bladder could be an attractive approach for the treatment OAB that can avoid systemic side effects due to non-specific peripheral blockade of NGF expression. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e798 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naoki Kawamorita Pittsburgh, PA More articles by this author Mahendra Kashyap Pittsburgh, PA More articles by this author Vikas Tyagi Pittsburgh, PA More articles by this author Yoshio Sugino Pittsburgh, PA More articles by this author Michael Chancellor Royal Oak, MI More articles by this author Naoki Yoshimura Pittsburgh, PA More articles by this author Pradeep Tyagi Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...