Targeting P75 Neurotrophin Receptors Ameliorates Spinal Cord Injury-induced Detrusor Sphincter Dyssynergia in Mice

Overview

Journal Neurourol Urodyn

Date 2018 May 29

PMID 29806700

Citations 9

Authors

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

Affiliations

Soon will be listed here.

Abstract

Aims: To determine the role of p75 neurotrophin receptor (p75 ) and the therapeutic effect of the selective small molecule p75 modulator, LM11A-31, in spinal cord injury (SCI) induced lower urinary tract dysfunction (LTUD) using a mouse model.

Methods: Adult female T -T transected mice were gavaged daily with LM11A-31 (100 mg/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 in the detrusor layer of the mouse bladder and lamina II region of the dorsal horn of the lumbar-sacral (L -S ) 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 can moderate DSD and DO in SCI mice, may identify pathophysiological mechanisms, and have therapeutic potential in SCI patients.

Citing Articles

Axonal growth inhibitors and their receptors in spinal cord injury: from biology to clinical translation.

Sousa Chambel S, Cruz C Neural Regen Res. 2023; 18(12):2573-2581.

PMID: 37449592 PMC: 10358698. DOI: 10.4103/1673-5374.373674.

Targeting neurotrophin and nitric oxide signaling to promote recovery and ameliorate neurogenic bladder dysfunction following spinal cord injury - Mechanistic concepts and clinical implications.

Kanai A, Andersson K, Fry C, Yoshimura N Continence (Amst). 2023; 6.

PMID: 37389025 PMC: 10310066. DOI: 10.1016/j.cont.2023.100703.

Assessing Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury: Animal Models in Preclinical Neuro-Urology Research.

Doelman A, Streijger F, Majerus S, Damaser M, Kwon B Biomedicines. 2023; 11(6).

PMID: 37371634 PMC: 10294962. DOI: 10.3390/biomedicines11061539.

Targeting neurotrophin and nitric oxide signaling to treat spinal cord injury and associated neurogenic bladder overactivity.

Ikeda Y, Zabbarova I, Tyagi P, Hitchens T, Wolf-Johnston A, Wipf P Continence (Amst). 2023; 1.

PMID: 37207253 PMC: 10194419. DOI: 10.1016/j.cont.2022.100014.

Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury.

Shimizu N, Saito T, Wada N, Hashimoto M, Shimizu T, Kwon J Int J Mol Sci. 2023; 24(9).

PMID: 37175592 PMC: 10177842. DOI: 10.3390/ijms24097885.

References

Fowler C, Griffiths D, de Groat W . The neural control of micturition. Nat Rev Neurosci. 2008; 9(6):453-66. PMC: 2897743. DOI: 10.1038/nrn2401. View

Hass M, Sato C, Kopan R, Zhao G . Presenilin: RIP and beyond. Semin Cell Dev Biol. 2008; 20(2):201-10. PMC: 2693421. DOI: 10.1016/j.semcdb.2008.11.014. View

de Groat W, Yoshimura N . Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp Neurol. 2011; 235(1):123-32. PMC: 3580860. DOI: 10.1016/j.expneurol.2011.05.003. View

McCarthy C, Zabbarova I, Brumovsky P, Roppolo J, Gebhart G, Kanai A . Spontaneous contractions evoke afferent nerve firing in mouse bladders with detrusor overactivity. J Urol. 2009; 181(3):1459-66. PMC: 2899488. DOI: 10.1016/j.juro.2008.10.139. View

Birder L, Apodaca G, de Groat W, Kanai A . Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Physiol. 1998; 275(2):F226-9. DOI: 10.1152/ajprenal.1998.275.2.F226. View

Ochodnicky P, Cruz C, Yoshimura N, Cruz F . Neurotrophins as regulators of urinary bladder function. Nat Rev Urol. 2012; 9(11):628-37. DOI: 10.1038/nrurol.2012.178. View

Harrington A, Leiner B, Blechschmitt C, Arevalo J, Lee R, Morl K . Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc Natl Acad Sci U S A. 2004; 101(16):6226-30. PMC: 395951. DOI: 10.1073/pnas.0305755101. View

Meeker R, Williams K . Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol. 2014; 9(5):615-28. PMC: 4243516. DOI: 10.1007/s11481-014-9566-9. View

Merrill L, Gonzalez E, Girard B, Vizzard M . Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol. 2016; 13(4):193-204. PMC: 5257280. DOI: 10.1038/nrurol.2016.13. View

10.

Ikeda Y, Fry C, Hayashi F, Stolz D, Griffiths D, Kanai A . Role of gap junctions in spontaneous activity of the rat bladder. Am J Physiol Renal Physiol. 2007; 293(4):F1018-25. PMC: 3037091. DOI: 10.1152/ajprenal.00183.2007. View

11.

Vaidyanathan S, Krishnan K, Mansour P, Soni B, McDicken I . p75 nerve growth factor receptor in the vesical urothelium of patients with neuropathic bladder: an immunohistochemical study. Spinal Cord. 1998; 36(8):541-7. DOI: 10.1038/sj.sc.3100589. View

12.

Tep C, Lim T, Ko P, Getahun S, Ryu J, Goettl V . Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J Neurosci. 2013; 33(2):397-410. PMC: 3710149. DOI: 10.1523/JNEUROSCI.0399-12.2013. View

13.

Teng K, Felice S, Kim T, Hempstead B . Understanding proneurotrophin actions: Recent advances and challenges. Dev Neurobiol. 2010; 70(5):350-9. PMC: 3063094. DOI: 10.1002/dneu.20768. View

14.

Klinger M, Vizzard M . Role of p75NTR in female rat urinary bladder with cyclophosphamide-induced cystitis. Am J Physiol Renal Physiol. 2008; 295(6):F1778-89. PMC: 2604835. DOI: 10.1152/ajprenal.90501.2008. View

15.

Kullmann F, Clayton D, Ruiz W, Wolf-Johnston A, Gauthier C, Kanai A . Urothelial proliferation and regeneration after spinal cord injury. Am J Physiol Renal Physiol. 2017; 313(1):F85-F102. PMC: 5538841. DOI: 10.1152/ajprenal.00592.2016. View

16.

Longo F, Massa S . Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov. 2013; 12(7):507-25. DOI: 10.1038/nrd4024. View

17.

Apodaca G, Kiss S, Ruiz W, Meyers S, Zeidel M, Birder L . Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol. 2003; 284(5):F966-76. DOI: 10.1152/ajprenal.00359.2002. View

18.

Ochodnicky P, Michel M, Butter J, Seth J, Panicker J, Michel M . Bradykinin modulates spontaneous nerve growth factor production and stretch-induced ATP release in human urothelium. Pharmacol Res. 2013; 70(1):147-54. DOI: 10.1016/j.phrs.2013.01.010. View

19.

Simmons D, Belichenko N, Ford E, Semaan S, Monbureau M, Aiyaswamy S . A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice. Hum Mol Genet. 2017; 25(22):4920-4938. PMC: 5418739. DOI: 10.1093/hmg/ddw316. View

20.

Park A . Alzheimer's From A New Angle. Time. 2016; 187(6-7):64-8, 70. View