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

Spinal cord injury (SCI) affects approximately 90% of individuals with neurogenic lower urinary tract (LUT) dysfunction, predominantly manifesting as neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia (DSD). These conditions significantly impact quality of life and can lead to serious complications like upper urinary tract damage. Current treatments for SCI-induced LUT disorders primarily focus on managing symptoms, with limited options for addressing the underlying pathophysiological mechanisms. Antimuscarinics are frequently used as a first-line treatment, although adverse effects often limit their efficacy. Other therapeutic options include α1-adrenoceptor antagonists, β3-adrenoceptor agonists, and toxins, each with their own limitations and side effects. This review summarizes the findings from a workshop that investigated novel therapeutic strategies targeting neurotrophin and nitric oxide (NO) signaling pathways to promote spinal cord repair and ameliorate neurogenic bladder dysfunction. The workshop explored a two-pronged approach focusing on (1) repairing damage to the spinal cord itself and (2) normalizing bladder wall functions to improve LUT function. The review delves into the pathophysiology of NDO and DSD to gain a deeper understanding of the mechanisms underlying these conditions and how emerging therapies might function. The ultimate goal is to develop treatments that restore normal bladder function rather than simply suppress abnormal activity.

The workshop reviewed existing pharmacological treatments for SCI-induced LUT disorders, including antimuscarinics, α1-adrenoceptor antagonists, β3-adrenoceptor agonists, and toxins. Limitations of current treatments, such as adverse effects and limited efficacy, were discussed. The literature supporting the use of β3-adrenoceptor agonists (mirabegron and vibegron) for NDO was reviewed, alongside studies demonstrating the efficacy, but limitations, of toxins like intravesical capsaicin and resiniferatoxin. The review also considered future treatment alternatives such as small molecule transient receptor potential channel antagonists and inosine. Existing research on the role of nitric oxide (NO) and its potential therapeutic benefits through the soluble guanylate cyclase (sGC) pathway and phosphodiesterase 5 (PDE5) inhibitors were also examined. This section highlighted the need for exploring less-explored therapeutic targets, such as attenuation of spinal cord damage and regulation of mechanosensitive afferent activity in DSD.

This paper presents a summary of the workshop "Targeting Neurotrophin and Nitric Oxide Signaling to Promote Recovery and Ameliorate Neurogenic Bladder Dysfunction Following Spinal Cord Injury - Mechanistic Concepts and Clinical Implications," held at the International Continence Society (ICS) 2022 Vienna Meeting. The methodology involved a review of presentations delivered at the workshop. The workshop presentations covered a range of topics related to the pathophysiology and treatment of SCI-induced LUT dysfunction. This included a detailed examination of the role of neurotrophin and nitric oxide signaling pathways in the development and progression of NDO and DSD following SCI. Presentations explored the potential benefits of using a combination of pharmacological agents targeting different stages of SCI-induced pathology to improve functional outcomes. Specific agents discussed included LM11A-3, a p75 neurotrophin receptor modulator; LM22B-10, which promotes neuronal growth by activating Trk receptors; and cinaciguat, an sGC activator. The presentations also investigated potential targets within the bladder wall itself, such as purinergic pathways and mechanosensitive afferents, to develop more targeted therapies. The review integrates and summarizes information presented by various experts in the field, focusing on the mechanistic concepts and clinical implications of targeting neurotrophin and nitric oxide signaling. The data presented is primarily based on preclinical studies in animal models, providing a foundation for future clinical trials to translate these findings to human patients.

The workshop highlighted the potential of a three-pronged pharmacological approach to treat SCI-induced LUT dysfunction: Firstly, attenuating spinal cord damage using LM11A-3 (p75 NTR modulator) to protect against early cell death, followed by LM22B-10 (Trk receptor activator) to promote neural remodeling and repair. Secondly, enhancing spinal cord perfusion and reducing scarring through the use of cinaciguat, an sGC activator, which boosts cGMP production even under oxidative stress. This process enhances angiogenesis and improves mitochondrial function. Thirdly, targeting the bladder itself by modulating purinergic pathways to reduce excess contractile activity and targeting mechanosensitive afferents to alleviate DSD. The workshop's findings emphasized the crucial role of purinergic signaling in NDO, showing an increased frequency-dependent release of ATP in both animal models and human patients with SCI. This is compounded by decreased ATP metabolism by ectonucleotidases and increased release from non-neuronal sources like the urothelium. Furthermore, the excessive ATP levels can amplify spontaneous detrusor contractions through enhanced gap junction coupling and stimulate mechanosensitive nerves, perpetuating the cycle of overactivity. In the case of DSD, the upregulation of neurotrophic factors, specifically BDNF, activates mechanosensitive Aδ fiber afferent pathways. This suggests potential therapeutic interventions such as anti-neurotrophic factor therapies, subpopulation-specific viral vectors targeting Aδ-fibers, and mechanosensitive channel blockers (ASIC or Piezo2 channels). The findings underscore the complex interplay between central nervous system damage and peripheral bladder pathology, suggesting that effective treatment strategies will require a combination of approaches targeting both.

The workshop findings suggest that a multi-target approach is essential for effectively managing SCI-induced LUT dysfunction. Targeting both the spinal cord lesion and the downstream bladder dysfunction offers a more comprehensive strategy than simply addressing symptoms. The preclinical data presented strongly support the potential of the proposed pharmacological agents, however further research is needed to translate these promising results into clinically effective therapies for human patients. The combination of neurotrophin and NO signaling modulation presents a novel therapeutic paradigm, moving beyond symptom management to focus on the underlying causes of neurogenic bladder dysfunction. This targeted approach offers the potential for significant improvements in quality of life for individuals living with SCI and LUT disorders. The data also highlights the crucial role of purinergic pathways and mechanosensitive afferents in mediating bladder overactivity and dysfunction. This reinforces the importance of developing specific therapies that target these pathways in conjunction with spinal cord repair strategies.

The workshop highlighted the significant potential for novel therapies targeting neurotrophin and NO signaling to ameliorate neurogenic bladder dysfunction after SCI. A multi-faceted approach targeting both spinal cord repair and bladder pathology appears promising. Further research, including clinical trials, is warranted to validate these findings and translate them into effective treatments for patients. Future research should focus on optimizing the combination and timing of these therapies and thoroughly investigating their potential synergistic effects and to examine the long-term efficacy and safety profiles of these agents in human patients.

The primary limitation is that much of the presented data is based on preclinical studies in animal models of SCI. While these studies offer valuable insights into the underlying mechanisms and potential therapeutic targets, the translation of these findings to human patients remains to be determined. Clinical trials are necessary to validate the efficacy and safety of these novel therapies in humans. Also, the heterogeneity of SCI and its associated bladder dysfunction necessitates further research into individual patient responses and potential biomarkers to personalize treatment strategies. The complexity of the interplay between the central and peripheral nervous systems in this condition poses a challenge in developing comprehensive and effective treatment strategies.