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

The review summarizes the ICS 2022 workshop on strategies to manage lower urinary tract dysfunction after spinal cord injury. It first reviews current therapeutic options for LUT dysfunction post-SCI, then describes two future target domains: (1) repair and mitigation of spinal cord damage and (2) normalization of bladder wall functions driving abnormal LUT behavior. The review also provides deeper discussions of the pathophysiology of neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia (DSD) to elucidate mechanisms underlying current and emerging therapies.

Approximately 90% of individuals with SCI develop neurogenic LUT dysfunction. Major symptoms include NDO and DSD, which can raise intravesical pressure and risk upper tract and renal damage. Current pharmacotherapies include antimuscarinics (first-line, alone or in combination) but adverse effects such as dry mouth, constipation, and potential cognitive impairment can limit adherence. β3-adrenoceptor agonists (mirabegron, vibegron) show efficacy for NDO. α1-adrenoceptor antagonists are used to treat storage and voiding symptoms and autonomic dysreflexia. Intravesical neurotoxins (capsaicin, resiniferatoxin) have demonstrated efficacy but are limited by adverse effects and handling challenges; they are currently not in routine use. Intradetrusor botulinum toxin A is an effective option for NDO refractory to oral agents and in patients who can perform clean intermittent catheterization. Emerging therapies include TRP channel antagonists and inosine. Agents modulating nitric oxide–sGC–cGMP signaling are of particular interest: PDE5 inhibitors (increasing cGMP by reducing its degradation) have proof-of-concept efficacy, and sGC activators like cinaciguat may be advantageous under oxidative stress where native sGC is downregulated. Historically, most treatments target the bladder and outlet; less explored are strategies to attenuate spinal cord damage itself and to modulate mechanosensitive afferent activity relevant to DSD.

This is a narrative review of presentations from an ICS 2022 workshop. Evidence discussed spans preclinical mouse models of SCI (T8–T9 contusion/transection) and human tissue studies. Interventions include: (1) LM11A-31, a small-molecule modulator of p75 neurotrophin receptors, administered within days of injury to reduce apoptosis; (2) LM22B-10, a TrkB/C agonist administered over several weeks to promote neural remodeling and reduce scarring; and (3) cinaciguat, a heme-independent sGC activator to enhance cGMP signaling, improve mitochondrial respiratory control, and increase vascularization near the injury. Experimental approaches referenced include MRI and diffusion tensor imaging for spinal cord integrity and axonal tract continuity; cystometrogram–external urethral sphincter electromyogram (CMG–EUS–EMG) recordings in mice to characterize NDO and DSD; electrical field stimulation studies of mouse and human detrusor to assess frequency-dependent acetylcholine and ATP release; optical mapping of calcium transients in bladder mucosa; assessments of atropine resistance; and analyses of mechanosensitive channel expression (e.g., ASIC, Piezo2) in dorsal root ganglia over time after SCI.

- Neurotrophin signaling modulation: Pathologic conditions after SCI increase proneurotrophin release and p75 NTR activation, triggering apoptosis. LM11A-31 binds the p75 NTR–sortilin complex to reduce early post-injury cell death when given within days. LM22B-10 subsequently activates TrkB/C receptors over weeks, promoting neuronal growth/remodeling and reducing scarring, with improvements in NDO and DSD readouts in mouse CMG–EUS–EMG recordings. - Nitric oxide–sGC–cGMP pathway: sGC activity may be downregulated by NO-mediated feedback and oxidative stress after SCI. Cinaciguat, a heme-independent sGC activator, enhances cGMP signaling despite oxidative stress, improving mitochondrial respiratory control ratios and increasing vessel formation around the scar in mice, suggesting improved perfusion and protection against secondary injury. - Purinergic mechanisms in NDO: In rodent detrusor, nerve-evoked transmitter release is frequency dependent, with ATP release at lower frequencies. In normal human bladder, the purinergic component is minimal, but it re-emerges in SCI tissue, causing a leftward shift in frequency–response curves and atropine-resistant contractile components. Atropine resistance is attributed to reduced ATP metabolism (ectonucleotidase downregulation) and increased basal/stretch-induced ATP release from non-neuronal sources (urothelium). Elevated ATP potentiates autonomous detrusor contractions, amplified by enhanced gap junction coupling; these contractions can trigger mechanosensitive afferent firing, reinforcing reflex bladder contractions. - Bladder remodeling and fibrosis: Neurogenic injury is associated with urinary retention and inflammation, leading to excess collagen deposition, altered compliance, and reduced capacity. Bladder fibrosis is observed in SCI and congenital neuropathic conditions (e.g., myelomeningocele). - Mechanosensitive signaling in DSD: SCI above lumbosacral levels disrupts supraspinal control, initially causing areflexia and later NDO and DSD with inefficient voiding and high intravesical pressures. Upregulation of neurotrophic factors such as BDNF contributes to DSD via activation of mechanosensitive Aδ-fiber afferent pathways, distinct from C-fiber hyperexcitability underlying NDO. Targeting Aδ-afferents using subpopulation-specific viral vectors, inhibiting BDNF signaling, and blocking mechanosensitive channels (ASIC, Piezo2) are proposed avenues to alleviate DSD. - Therapeutic landscape: Existing treatments (antimuscarinics, β3 agonists, α1 blockers, botulinum toxin) manage symptoms but have limitations. PDE5 inhibitors show proof-of-concept benefits; sGC activators may offer advantages under oxidative stress. TRP channel antagonists and inosine are in development as additional modalities.

The workshop’s findings support a paradigm that complements symptom control with disease-modifying strategies targeting both the injured spinal cord and the downstream LUT pathophysiology. Early modulation of p75 NTR signaling may limit apoptotic cascades and secondary degeneration, while subsequent activation of Trk receptors can promote neural remodeling and functional recovery. Concurrently, augmenting NO–sGC–cGMP signaling with cinaciguat may counteract oxidative stress–induced sGC downregulation, improve mitochondrial function, and enhance vascular perfusion to support tissue repair. On the LUT side, purinergic upregulation, atropine-resistant contractions, and enhanced intercellular coupling contribute to NDO and can drive afferent sensitization; interventions that reduce ATP signaling or gap junction–mediated amplification may improve storage function without broadly suppressing normal activity. For DSD and inefficient voiding, the identification of BDNF-driven Aδ-afferent mechanosensitivity and mechanotransduction via ASIC and Piezo2 suggests more specific targets than global anticholinergic or neuromodulatory approaches. Overall, staged combination strategies—early cord-protective and pro-regenerative agents with later bladder- and afferent-targeted therapies—may best restore function and reduce pathological consequences.

The review highlights mechanistic targets to promote recovery after SCI and ameliorate neurogenic bladder dysfunction, emphasizing staged interventions: early p75 NTR modulation (LM11A-31) to reduce apoptosis, later TrkB/C activation (LM22B-10) to foster remodeling, and sGC activation (cinaciguat) to improve mitochondrial function and angiogenesis. In the LUT, addressing purinergic signaling, gap junction–mediated spontaneous activity, fibrosis, and mechanosensitive Aδ-afferent pathways (including BDNF, ASIC, Piezo2) offers avenues to treat NDO and DSD more specifically. Future research should include rigorous preclinical-to-clinical translation, optimization of timing and combinations of neurotrophin and NO–sGC targeted therapies, validation of mechanosensitive channel blockers and afferent-specific strategies, and clinical trials assessing efficacy and safety in diverse SCI populations.

This article is a narrative review of a workshop and not a primary clinical trial. Many findings are derived from animal models (e.g., mouse T8–T9 contusion/transection) or ex vivo human tissue studies, and proposed therapies (e.g., LM11A-31, LM22B-10, cinaciguat, mechanosensitive channel blockers) remain experimental or at proof-of-concept stages. Translation to clinical practice, optimal timing and dosing, long-term safety, and efficacy in heterogeneous human SCI populations require further investigation. Specific treatments for DSD are currently lacking, underscoring the need for targeted clinical development.