Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury
Jae Cheon Ryu, … , Margaret A. Vizzard, Sung Ok Yoon
Jae Cheon Ryu, … , Margaret A. Vizzard, Sung Ok Yoon
Published March 26, 2018
Citation Information: J Clin Invest. 2018;128(5):1772-1786. https://doi.org/10.1172/JCI97837.
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Research Article Neuroscience

Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury

Abstract

Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro–nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase–positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Authors

Jae Cheon Ryu, Katharine Tooke, Susan E. Malley, Anastasia Soulas, Tirzah Weiss, Nisha Ganesh, Nabila Saidi, Stephanie Daugherty, Uri Saragovi, Youko Ikeda, Irina Zabbarova, Anthony J. Kanai, Mitsuharu Yoshiyama, H. Francis Farhadi, William C. de Groat, Margaret A. Vizzard, Sung Ok Yoon

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Figure 6

Systemic LM11A-31 greatly improves bladder function after SCI in mice.

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Systemic LM11A-31 greatly improves bladder function after SCI in mice. (...
(A) Representative bladder function recordings in conscious, unrestrained vehicle- or LM11A-31–treated mice with continuous intravesical instillation of saline with an open outlet at 28 days after injury. Upper recordings were from SCI mice that were treated with vehicle, while lower ones were from SCI mice that were treated with 100 mg/kg LM11A-31. Boxed areas: Representative single-fill cystometry recordings (arrow, infusion start) in conscious, unrestrained vehicle- or LM11A-31–treated mice from 2 different experiments. (B) After SCI, LM11A-31 significantly reduced bladder capacity, reaching that of spinal-intact mice. (C) Micturition pressures (threshold, average, maximum) were significantly reduced compared with those in vehicle-treated mice. (D and E) Infused volume and intermicturition intervals were reduced compared with those in vehicle-treated mice in both spinal-intact and SCI groups. (F) Greater numbers of mice treated with LM11A-31 recovered automatic micturition significantly earlier than vehicle-treated mice after SCI. Time (days) to recovery of automatic micturition for 2 groups was compared using a 2-tailed unpaired Student’s t test. P ≤ 0.05 was considered statistically significant. Comparisons of cystometric parameters among groups (B–E) were made using ANOVA. When F ratios exceeded the adjusted critical value (P ≤ 0.0125), Bonferroni’s multiple-comparisons test was used to compare means among groups.