Introduction: Stress Urinary Incontinence (SUI), urine leakage from an increase in abdominal pressure, affects 30% of women over the age of 40. The primary risk factor is childbirth. As the baby's head passes through the birth canal, it injures the pudendal nerve (PN), which innervates the external urethral sphincter (EUS) that provides urethral resistance and maintains continence. Increased PN motor latency in women with SUI after childbirth suggests that PN function and recovery are important to continence. A dual PN crush (PNC) and vaginal distension (VD) childbirth injury model has been shown to delay recovery compared to either injury alone as well as dysregulate EUS expression of brain-derived neurotrophic factor (BDNF). BDNF administration after dual injury has been shown to accelerate recovery, suggesting BDNF is necessary for recovery. To test the hypothesis that BDNF is essential for functional recovery in the dual injury SUI model, this project used tyrosine kinase B (TrkB), the receptor for BDNF, to bind free BDNF and inhibit the BDNF regeneration pathway.
Methods: Thirteen female Sprague-Dawley rats received sham PNC, sham VD and osmotic pumps containing saline (sham injury). Thirteen additional rats received PNC & VD and osmotic pumps with saline (injury + saline) and 14 rats received PNC & VD and osmotic pumps with Fc-TrkB (injury + TrkB). Six weeks after injury, animals underwent leak point pressure (LPP) testing with EUS electromyography (EMG). A Welsh ANOVA with a Dunnett’s T3 post hoc test compared LPP and EUS EMG between groups with the injury + saline group as the control. P<0.05 indicated a statistically significant difference between groups. Urethras were harvested, fresh frozen and stained for axons and neuromuscular junctions (NMJs) to assess NMJ innervation in the EUS.
Results: Injury + TrkB LPP was significantly decreased compared to injury + saline. Additionally, injury + TrkB EUS EMG amplitude trended toward a significant decrease (p=0.06) compared to injury + saline. The sham injury was not significantly different from injury + saline in either LPP or EUS EMG, indicating normal spontaneous recovery occurs by six weeks. NMJ staining showed that TrkB inhibited NMJ reinnervation after dual injury.
Conclusions: This study demonstrates that BDNF is essential for recovery and reinnervation of EUS NMJs in this SUI model. These results demonstrate the importance of BDNF to neuromuscular recovery after childbirth. Women could potentially benefit from treatments aimed to increase BDNF.
Source of Funding: US Dept of Veterans Affairs and Cleveland Clinic
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