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

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

doi:10.1172/jci97837

Cited by 40 publications

(28 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…After SCI, BDNF levels are enhanced in the spinal cord and TrkB expression and activation are also increased in lumbosacral DRG neurons and spinal tissue [74,75,201]. The expression of the low-affinity receptor p75 is also altered following SCI and recent studies have demonstrated the importance of this receptor in lower urinary dysfunction following SCI and support the use of p75 antagonists for treatment [187,202]. Recent findings suggested that this increase in BDNF levels contribute, in an early phase post-SCI, to downregulate abnormal axonal growth and prevent urinary dysfunction [203] possibly by inhibiting NGF-mediated neuronal sprouting [204,205].…”

Section: Spinal Cord Injury and Visceral Dysfunction: Are Ngf And Bdnmentioning

confidence: 87%

“…influence in enhancing Trk specificity to their NT ligands, improving neuronal survival and differentiation in healthy conditions. In pathological conditions, p75 preferentially binds to pro-NTs, activating apoptotic pathways via JNK and NFκ-β [147,186], in a process that also requires sortilin [187,188].…”

Section: Downstream Targets Of Ngf and Bdnfmentioning

confidence: 99%

“…In the context of bladder inflammation and BPS/IC, activation of p75 has been linked to a reduction in bladder reflex activity, in contrast to TrkA-mediated enhancement of bladder [41,42]. More recently, it was demonstrated that pro-NGF activity on p75 might contribute to detrusor sphincter dyssynergia (DSD) and bladder hyperactivity following spinal cord injury (SCI), suggesting that modulation of the p75 receptor might be of interest for the management of SCI patients [186,187].…”

Section: Downstream Targets Of Ngf and Bdnfmentioning

confidence: 99%

See 2 more Smart Citations

Partners in Crime: NGF and BDNF in Visceral Dysfunction

Coelho

Oliveira

Antunes-Lopes

et al. 2019

View full text Add to dashboard Cite

: Neurotrophins (NTs), particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), have attracted increasing attention in the context of visceral function for some years. Here, we examined the current literature and presented a thorough review of the subject. : After initial studies linking of NGF to cystitis, it is now well-established that this neurotrophin (NT) is a key modulator of bladder pathologies, including Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS. NGF is upregulated in bladder tissue and its blockade results in major improvements on urodynamic parameters and pain. Further studies expanded showed that NGF is also an intervenient in other visceral dysfunctions such as endometriosis and Irritable Bowel Syndrome (IBS). : More recently, BDNF was also shown to play an important role in the same visceral dysfunctions, suggesting that both NTs are determinant factors in visceral pathophysiological mechanisms. Manipulation of NGF and BDNF improves visceral function and reduce pain, suggesting that clinical modulation of these NTs may be important; however, much is still to be investigated before this step is taken. : Another active area of research is centered on urinary NGF and BDNF. Several studies show that both NTs can be found in the urine of patients with visceral dysfunction in much higher concentration than in healthy individuals, suggesting that they could be used as potential biomarkers. However, there are still technical difficulties to be overcome, including the lack of a large multicentre placebo-controlled studies to prove the relevance of urinary NTs as clinical biomarkers.

show abstract

Section: Spinal Cord Injury and Visceral Dysfunction: Are Ngf And Bdnmentioning

confidence: 87%

Section: Downstream Targets Of Ngf and Bdnfmentioning

confidence: 99%

Section: Downstream Targets Of Ngf and Bdnfmentioning

confidence: 99%

See 1 more Smart Citation

Partners in Crime: NGF and BDNF in Visceral Dysfunction

Coelho

Oliveira

Antunes-Lopes

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Recent reports have demonstrated that the process of SCI recovery can be affected at the absence of pro-nerve growth factors and the presence of axonal growth inhibitors, both of which hinder the recovery of SCI. [2] Be it the structure or function of cortical neurons, the two causes are of vital importance for the corticospinal tracts. It has been reported the interference of axonal growth inhibitors may function as potential targets for rehabilitation and regeneration of the damaged corticospinal tracts.…”

Section: Introductionmentioning

confidence: 99%

Exosome-Mediated siRNA pool Inhibits Axonal Growth Inhibitor in Cortical Neurons of Spinal Cord Injury in Rats

Liao¹,

Ming²,

Guo³

2020

Preprint

View full text Add to dashboard Cite

Background: As exosomes have been confirmed as a reservoir of siRNAs involved in certain diseases, the current study aims to investigate whether exosomal-siRNA could exert a protective role in spinal cord injury (SCI). Methods and Results: Exosomes in our experiment were isolated from lysosomal membrane-associated protein 2b (Lamp2b) overexpression HEK 293T cells, and purity of exosomes was characterized by the expression of CD9, CD47, and CD63 via western blot. Furthermore, the siRNA pool contains four siRNAs including siRNA-NgR, siRNA-LINGO-1, siRNA-Troy, and siRNA-PTEN was loaded to the exosomes, which indicated a significant role for the siRNA pool in reducing the expression of axon growth inhibitory factors. Upon the completion of loading into exosomes (exo-siRNA pool), the exo-siRNA pool was injected into primary cortical neurons of the SCI model in rats before cell proliferation and Rho expression were determined With the results revealed that purified addition could be applied to future experiments. The exo-siRNA pooled transfection caused downregulation of axon growth suppressors in primary cortical neurons including Nogo receptors (NgR), leucine-rich repeats and immunoglobulin domain-containing protein 1 (LINGO-1), Troy, and phosphatase and tenson homolog (PTEN). Cell proliferation and Rho expression of primary cortical neurons inhibited the expression of axonal growth inhibitors in rats with SCI by transfecting exogenous Sirna. Conclusion: This study confirmed that exosomes derived from Lamp2b overexpression HEK 293T cells facilitated both the recovery of functions and the survival of neurons when being loaded with the siRNA pool.

show abstract

“…Interestingly, the precursor form of NGF, proNGF, is the main NGF found in adult human brain (Al-Shawi et al, 2007), and proNGF overexpression is associated with sympathetic and cholinergic system degeneration in animal models (Cuello, 2012). ProNGF has also been shown to be implicated in bladder dysfunction (Ryu et al, 2018). Moreover, loss of modulatory inputs arising from SNc and VTA dopaminergic neurons can affect brain micturition centers in a manner to negatively impact bladder function (Kitta et al, 2008; Soler et al, 2011; Yoshimura et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Parkinsonian GM2 synthase knockout mice lacking mature gangliosides develop urinary dysfunction and neurogenic bladder

Gil-Tommee

Vidal-Martinez

Reyes

et al. 2019

Experimental Neurology

View full text Add to dashboard Cite

Parkinson’s disease is a neurodegenerative disorder that reduces a patients’ quality of life by the relentless progression of motor and non-motor symptoms. Among the non-motor symptoms is a condition called neurogenic bladder that is associated with detrusor muscle underactivity or overactivity occurring from neurologic damage. In Parkinson’s disease, Lewy-body-like protein aggregation inside neurons typically contributes to pathology. This is associated with dopaminergic neuron loss in substantia nigra pars compacta (SNc) and in ventral tegmental area (VTA), both of which play a role in micturition. GM1 gangliosides are mature glycosphingolipids that enhance normal myelination and are reduced in Parkinson’s brain. To explore the role of mature gangliosides in vivo, we obtained GM2 Synthase knockout (KO) mice, which develop parkinsonian pathology including a loss of SNc dopaminergic neurons, which we reconfirmed. However, bladder function and innervation have never been assessed in this model. We compared GM2 Synthase KO and wild type (WT) littermates’ urination patterns from 9–19 months of age by counting small and large void spots produced during 1 hour tests. Because male and female mice had different patterns, we evaluated data by sex and genotype. Small void spots were significantly increased in 12–16 month GM2 Synthase KO females, consistent with overactive bladder. Similarly, at 9–12 month GM2 KO males tended to have more small void spots than WT males. As GM2 Synthase KO mice aged, both females and males had fewer small and large void spots, consistent with detrusor muscle underactivity. Ultrasounds confirmed bladder enlargement in GM2 Synthase KO compared to WT mice. Tyrosine hydroxylase (TH) immunohistochemistry revealed significant dopaminergic loss in GM2 Synthase KO VTA and SNc, and a trend toward TH loss in GM2 KO periaqueductal gray (PAG) micturition center. Levels of the nerve growth factor precursor, proNGF, were significantly increased in GM2 Synthase KO bladders and transmission electron micrographs established atypical myelination of pelvic ganglion innervation in GM2 Synthase KO bladders. Cumulatively, our findings provide the first evidence that mature ganglioside loss affects micturition center TH neurons as well as proNGF dysregulation and innervation of the bladder. Thus, identifying therapies that will counteract these effects could be beneficial for those suffering from Parkinson’s disease and related disorders.

show abstract

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

Cited by 40 publications

References 40 publications

Partners in Crime: NGF and BDNF in Visceral Dysfunction

Partners in Crime: NGF and BDNF in Visceral Dysfunction

Exosome-Mediated siRNA pool Inhibits Axonal Growth Inhibitor in Cortical Neurons of Spinal Cord Injury in Rats

Parkinsonian GM2 synthase knockout mice lacking mature gangliosides develop urinary dysfunction and neurogenic bladder

Contact Info

Product

Resources

About