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

doi:10.1002/nau.23722

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 journal › Article (Academic Journal) › peer-review

4 Citations (Scopus)

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Abstract

Aims: To determine the role of p75 neurotrophin receptor (p75^NTR) and the therapeutic effect of the selective small molecule p75^NTR 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 p75^NTRs 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 p75^NTRs can moderate DSD and DO in SCI mice, may identify pathophysiological mechanisms, and have therapeutic potential in SCI patients.

Original language	English
Number of pages	10
Journal	Neurourology and Urodynamics
Early online date	28 May 2018
DOIs	https://doi.org/10.1002/nau.23722
Publication status	E-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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10.1002/nau.23722

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Zabbarova, I. V., Ikeda, Y., Carder, E. J., Wipf, P., Wolf-Johnston, A. S., Birder, L. A., Yoshimura, N., Getchell, S. E., Almansoori, K., Tyagi, P., Fry, C. H., Drake, M. J., & Kanai, A. J. (2018). Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. Neurourology and Urodynamics. https://doi.org/10.1002/nau.23722

Zabbarova, Irina V. ; Ikeda, Youko ; Carder, Evan J. ; Wipf, Peter ; Wolf-Johnston, Amanda S. ; Birder, Lori A. ; Yoshimura, Naoki ; Getchell, Samuel E. ; Almansoori, Khalifa ; Tyagi, Pradeep ; Fry, Christopher H. ; Drake, Marcus J. ; Kanai, Anthony J. / Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. In: Neurourology and Urodynamics. 2018.

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title = "Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice",

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.",

keywords = "LM11A-31, Lower urinary tract dysfunction/symptoms (LUTD/LUTS), Neurodegeneration, Neurogenic bladder dysfunction, Proneurotrophins",

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

year = "2018",

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doi = "10.1002/nau.23722",

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Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. / Zabbarova, Irina V.; Ikeda, Youko; Carder, Evan J.; Wipf, Peter; Wolf-Johnston, Amanda S.; Birder, Lori A.; Yoshimura, Naoki; Getchell, Samuel E.; Almansoori, Khalifa; Tyagi, Pradeep; Fry, Christopher H.; Drake, Marcus J.; Kanai, Anthony J.

In: Neurourology and Urodynamics, 28.05.2018.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

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AU - Zabbarova, Irina V.

AU - Ikeda, Youko

AU - Carder, Evan J.

AU - Wipf, Peter

AU - Wolf-Johnston, Amanda S.

AU - Birder, Lori A.

AU - Yoshimura, Naoki

AU - Getchell, Samuel E.

AU - Almansoori, Khalifa

AU - Tyagi, Pradeep

AU - Fry, Christopher H.

AU - Drake, Marcus J.

AU - Kanai, Anthony J.

PY - 2018/5/28

Y1 - 2018/5/28

N2 - 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.

AB - 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.

KW - LM11A-31

KW - Lower urinary tract dysfunction/symptoms (LUTD/LUTS)

KW - Neurodegeneration

KW - Neurogenic bladder dysfunction

KW - Proneurotrophins

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