Neurotrophin therapy improves recovery of the neuromuscular continence mechanism following simulated birth injury in rats

Abstract

Aims Stress Urinary Incontinence (SUI) affects women both acutely and chronically after vaginal delivery. Current SUI treatments assume the neuromuscular continence mechanism, comprised of the pudendal nerve (PN) and external urethral sphincter (EUS), is either intact or irreparable. This study investigated the ability of neurotrophin therapy to facilitate recovery of the neuromuscular continence mechanism. Methods Virgin, Sprague Dawley rats received simulated childbirth injury or sham injury and treatment with continuous infusion of brain derived neurotrophic factor (BDNF) or saline placebo to the site of PN injury. Continence was assessed by leak point pressure (LPP) and EUS electromyography (EMG) 14 and 21 days after injury. Structural recovery was assessed histologically. Molecular assessment of the muscular and neuroregenerative response was determined via measurement of EUS BDNF and PN βII-tubulin expression respectively, 4, 8, and 12 days after injury. Results Following injury, LPP was significantly reduced with saline compared to either BDNF treatment or sham injury. Similarly, compared to sham injury, resting EUS EMG amplitude and firing rate, as well as amplitude during LPP were significantly reduced with saline but not BDNF treatment. Histology confirmed improved EUS recovery with BDNF treatment. EUS BDNF and PN βII-tubulin expression demonstrated that BDNF treatment improved the neurogenerative response and may facilitate sphincteric recovery. Conclusions Continuous targeted neurotrophin therapy accelerates continence recovery after simulated childbirth injury likely through stimulating neuroregeneration and facilitating EUS recovery and re-innervation. Neurotrophins or other therapies targeting neuromuscular regeneration may be useful for treating SUI related to failure of the neuromuscular continence mechanism.

Effects of acute selective pudendal nerve electrical stimulation after simulated childbirth injury

“…Generally, BDNF downregulation after muscle injury enables neuromuscular junction repair (46), but in childbirth injury is associated with delayed pudendal nerve regeneration after VD and PNC, both functionally and anatomically (27,40). Exogenous BDNF has been shown to improve urinary continence and EUS recovery after simulated birth injury (17).…”

“…BDNF upregulation likely promotes axonal regrowth since ␤ II -tubulin, which constitutes microtubules for neurofilaments for axon, when upregulated, indicates the regenerative effort of the neuron in response to injury (34). Moreover, expression of ␤ II -tubulin, as measured by mRNA levels, has been used to assess neurotrophin treatments (6,17,52). Therefore, ␤ IItubulin upregulation is evidence of pudendal nerve regeneration, whereas BDNF upregulation suggests it is promoted by the electrical stimulation.…”

“…Decreased neurotrophin expression in the EUS and delayed functional recovery of the urethra and pudendal nerve have been demonstrated in a simulated childbirth injury model, consisting of both vaginal distension (VD) and pudendal nerve crush (PNC) (9,27,40). In addition, treatment with BDNF accelerates recovery from simulated childbirth injury (17). Therefore, EUS injury in vaginal childbirth may inhibit recovery of pudendal nerve injury via insufficient upregulation of neurotrophins in the EUS.…”

Regenerative medicine as a new therapeutic strategy for lower urinary tract dysfunction

“…[18][19][20] Takahashi et al reported on the efficacy of local b-FGF injections into damaged RS in female rats. 18 Gelatin hydrogels were used for sustained release of b-FGF.…”

“…Gill et al reported that continuous neurotrophin treatment using brain-derived neurotrophic factor accelerated continence recovery after simulated childbirth injury, stimulating neuroregeneration, and facilitating RS recovery and reinnervation. 19 Therefore, cytokine regulation might also be useful as a novel therapeutic modality for the treatment of urinary incontinence.…”