title: Novel therapeutic approach for neurogenic erectile dysfunction: effect of neurotrophic tyrosine kinase receptor type 1 monoclonal antibody.
abstract: BACKGROUND
  Erectile dysfunction (ED) is a major health issue in aged populations, and neurogenic ED is particularly difficult to treat. Novel therapeutic approaches are needed for treatment of neurogenic ED of peripheral origin.
  
  
  OBJECTIVE
  To investigate the therapeutic effects of a neurotrophic tyrosine kinase receptor type 1 monoclonal antibody (TrkA-mAb) on erectile function and sexual behavior in a rat model of cavernous nerve injury (CNI).
  
  
  METHODS
  In one experiment, 84 male rats were randomly assigned to seven groups. The groups underwent either CNI or sham surgery, subsequent injection into the major pelvic ganglion (IMPG) of phosphate-buffered saline (PBS), an immunoglobulin G (IgG) control, or TrkA-mAb, and then intracavernosal (IC) injection of either PBS or varying TrkA-mAb concentrations immediately after surgery and then 1 wk later. Erectile function was assessed and histologic/molecular analyses were performed at 6 wk after surgery. In a second experiment, 36 male rats were randomly divided into three groups. The groups underwent CNI or sham surgery and then IC injection of PBS, IgG, or TrkA-mAb immediately after surgery and for 5 wk thereafter. At 6 wk after surgery, the performance of the rats in sexual behavior tests was videotaped.
  
  
  METHODS
  CNI or sham surgery; IMPG of PBS, IgG, or TrkA-mAb; IC injection of PBS or TrkA-mAb.
  
  
  METHODS
  The intracavernous pressure response to cavernous nerve electrostimulation was measured and midpenile cross-sections were histologically examined. Western blotting (WB) of cavernous tissue protein was performed. Rats were assessed for chasing, mounting, intromission, and ejaculation behaviors during sexual behavior tests. The data were analyzed using one-way analysis of variance followed by the Tukey-Kramer t test.
  
  
  CONCLUSIONS
  Recovery of erectile function of varying degrees was observed in the TrkA-mAb groups. TrkA-mAb treatment significantly suppressed tyrosine hydroxylase-positive nerve fibers in the corpus cavernosum and enhanced neuronal nitric oxide synthase-positive fibers in the dorsal nerve. The ratio of smooth muscle to collagen in the corpus cavernosum was significantly improved in TrkA-mAb treatment groups compared to PBS vehicle and IgG control groups. WB confirmed these biological changes. There was a nonsignificant increase in the average number of intromissions and ejaculations in the TrkA-mAb group. The study limitations include small sample size, variability in sexual behavior, lack of data on the neuromuscular mechanism involved, and lack of information of the role of neurotrophins or cytokines in regeneration.
  
  
  CONCLUSIONS
  TrkA-mAb successfully inhibits sympathetic nerve regeneration, leads to parasympathetic nerve regeneration, and has therapeutic effects on ED and sexual behavior disorder in a rat model of CNI.
  
  
  RESULTS
  This report provides strong evidence that a neurotrophic tyrosine kinase receptor type 1 monoclonal antibody (TrkA-mAb) inhibits sympathetic nerve regeneration, leads to parasympathetic nerve regeneration, and has therapeutic effects on erectile dysfunction and sexual behavior disorder in a rat model of cavernous nerve injury. The results raise the possibility that human patients with neurogenic erectile dysfunction may respond to TrkA-mAb in a manner that parallels the response seen in our rodent study.
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Guiting
authors.initials: G
authors.lastname: Lin
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA; Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing, P.R. China.
authors.forename: Huixi
authors.initials: H
authors.lastname: Li
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA; Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing, P.R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA; Department of Urology, School of Medicine, Capital Medical University, Beijing, P.R. China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Uwais
authors.initials: U
authors.lastname: Zaid
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Sanford
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Tu
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Wu
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA; Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Tian
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Kotanides
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Guifang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Ning
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Banie
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Ching-Shwun
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: deng_gary_g@lilly.com.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Deng
authors.affiliation: Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA. Electronic address: tlue@urology.ucsf.edu.
authors.forename: Tom F
authors.initials: TF
authors.lastname: Lue
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects*; D010410:Penile Erection / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000276:immunology*; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D020917:Receptor, trkA
keywords: Cavernous nerve injury; Nerve regeneration; Neurogenic erectile dysfunction of peripheral origin; Sexual behavior; Tyrosine kinase receptor type 1 monoclonal antibody