Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice

Irina V. Zabbarova, Youko Ikeda, Evan J. Carder, Peter Wipf, Amanda S. Wolf-Johnston, Lori A. Birder, Naoki Yoshimura, Samuel E. Getchell, Khalifa Almansoori, Pradeep Tyagi, Christopher H. Fry, Marcus J. Drake, Anthony J. Kanai*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
220 Downloads (Pure)

Abstract

Aims: To determine the role of p75 neurotrophin receptor (p75NTR) and the therapeutic effect of the selective small molecule p75NTR modulator, LM11A-31, in spinal cord injury (SCI) induced lower urinary tract dysfunction (LTUD) using a mouse model. Methods: Adult female T8-T9 transected mice were gavaged daily with LM11A-31 (100mg/kg) for up to 6 weeks, starting 1 day before, or 7 days following injury. Mice were evaluated in vivo using urine spot analysis, cystometrograms (CMGs), and external urethral sphincter (EUS) electromyograms (EMGs); and in vitro using histology, immunohistochemistry, and Western blot. Results: Our studies confirm highest expression of p75NTRs in the detrusor layer of the mouse bladder and lamina II region of the dorsal horn of the lumbar-sacral (L6-S1) spinal cord which significantly decreased following SCI. LM11A-31 prevented or ameliorated the detrusor sphincter dyssynergia (DSD) and detrusor overactivity (DO) in SCI mice, significantly improving bladder compliance. Furthermore, LM11A-31 treatment blocked the SCI-related urothelial damage and bladder wall remodeling. Conclusion: Drugs targeting p75NTRs can moderate DSD and DO in SCI mice, may identify pathophysiological mechanisms, and have therapeutic potential in SCI patients.

Original languageEnglish
Number of pages10
JournalNeurourology and Urodynamics
Early online date28 May 2018
DOIs
Publication statusE-pub ahead of print - 28 May 2018

Structured keywords

  • Centre for Surgical Research

Keywords

  • LM11A-31
  • Lower urinary tract dysfunction/symptoms (LUTD/LUTS)
  • Neurodegeneration
  • Neurogenic bladder dysfunction
  • Proneurotrophins

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