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. 2023 Mar 5;24(5):4998.
doi: 10.3390/ijms24054998.

Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model

Brian M Balog  1   2   3 , Kangli Deng  1   2 , Tessa Askew  1   4 , Brett Hanzlicek  1   2 , Mei Kuang  1 , Margot S Damaser  1   2   5
Affiliations

Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model

Brian M Balog et al. Int J Mol Sci. .

Abstract

In women, stress urinary incontinence (SUI), leakage of urine from increased abdominal pressure, is correlated with pudendal nerve (PN) injury during childbirth. Expression of brain-derived neurotrophic factor (BDNF) is dysregulated in a dual nerve and muscle injury model of childbirth. We aimed to use tyrosine kinase B (TrkB), the receptor of BDNF, to bind free BDNF and inhibit spontaneous regeneration in a rat model of SUI. We hypothesized that BDNF is essential for functional recovery from the dual nerve and muscle injuries that can lead to SUI. Female Sprague-Dawley rats underwent PN crush (PNC) and vaginal distension (VD) and were implanted with osmotic pumps containing saline (Injury) or TrkB (Injury + TrkB). Sham Injury rats received sham PNC + VD. Six weeks after injury, animals underwent leak-point-pressure (LPP) testing with simultaneous external urethral sphincter (EUS) electromyography recording. The urethra was dissected for histology and immunofluorescence. LPP after injury and TrkB was significantly decreased compared to Injury rats. TrkB treatment inhibited reinnervation of neuromuscular junctions in the EUS and promoted atrophy of the EUS. These results demonstrate that BDNF is essential to neuroregeneration and reinnervation of the EUS. Treatments aimed at increasing BDNF periurethrally could promote neuroregeneration to treat SUI.

Keywords: TrkB; female; neuromuscular junction; reinnervation; urinary incontinence.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of functional outcomes. Examples of external urethral sphincter electromyography (EUS EMG; top) and corresponding bladder pressure (bottom) from each of the three groups 6 weeks after injury: sham dual injury treated with saline (Sham Injury); pudendal nerve crush (PNC) and vaginal distension (VD) injury treated with saline (Injury); and PNC + VD injury treated with tyrosine kinase B (TrkB) fusion chimera (Injury + TrkB). Scale bar represents 1 s. Each animal was tested individually, and LPP and EUS EMG were recorded simultaneously. Representative examples were chosen by being close to the respective means for both outcomes.
Figure 2
Figure 2
Leak-point pressure results. Leak-point pressure 6 weeks after sham injury treated with saline (Sham Injury); pudendal nerve crush (PNC) and vaginal distension (VD) injury treated with saline (Injury); or PNC + VD injury treated with tyrosine kinase B (TrkB) fusion chimera (Injury + TrkB). Each bar represents mean ± standard error of the data from 11–14 animals. There were 4–6 LPP tests per animal. A Welsh one-way analysis of variance (ANOVA) with a Dunnett’s T3 post hoc test was used to determine statistically significant differences (p < 0.05) compared to the Injury group. * indicates a statistically significant difference compared to the Injury group.
Figure 3
Figure 3
External urethral sphincter electromyography results. External urethral sphincter (EUS) electromyography (EMG) firing rate (A) and amplitude (B) 6 weeks after sham injury treated with saline (Sham Injury), pudendal nerve crush (PNC) and vaginal distension (VD) injury treated with saline (Injury), or PNC + VD injury treated with tyrosine kinase B (TrkB) fusion-chimera (Injury + TrkB). Each bar represents mean ± standard error of the data from 11–14 animals. There were 4–6 EUS EMG tests per animal. A Welsh one-way analysis of variance (ANOVA) with a Dunnett’s T3 post hoc test was used to determine statistically significant differences (p < 0.05) compared to the Injury group.
Figure 4
Figure 4
Effects of Tyrosine Kinase B functional chimera binding. Plasma concentration of unbound (A) brain-derived neurotrophic factor (BDNF) and (B) neurotrophin 4 (NT4) six weeks after pudendal nerve crush (PNC) and vaginal distension (VD) injury treated with saline (Injury), or PNC + VD injury treated with tyrosine kinase B (TrkB) fusion chimera (Injury + TrkB). Each bar represents the mean ± standard error of the mean of data from 8–12 animals in each group. A Mann–Whitney test was used to determine statistically significant differences. * indicates a statistically significant difference (p < 0.05) between the groups.
Figure 5
Figure 5
External urethral sphincter anatomy. Representative images of Masson’s stained urethral cross-sections 6 weeks after (A) sham dual injury treated with saline (Sham Injury); (B) pudendal nerve crush (PNC) and vaginal distension (VD) injury treated with saline (Injury); and (C) PNC + VD injury treated with tyrosine kinase B (TrkB) fusion-chimera (Injury + TrkB). Representative images of neuromuscular junction (NMJ) immunofluorescence 6 weeks after (D) sham injury, (E) injury, and (F) injury + TrkB. In Masson’s stained specimens (A–C), collagen was stained blue, and muscle cells were stained red. In immunofluorescence images (D–F), nerve axons are stained green, NMJs are stained red, and the muscle is stained blue. The green scale bar in panel (A) for Masson’s trichrome data is 100 µm. The white scale bar in panel (D) for immunofluorescence data is 20 µm. Green arrows indicate collagen, and the blue arrow indicates disrupted EUS.
Figure 6
Figure 6
Summary diagram. A normal external urethral sphincter (EUS) is innervated by the motor neurons of the pudendal nerve (PN), as shown in (A). An injured EUS and PN has decreased innervation, as shown in (B). Treatments that enhance the BDNF regenerative pathway could enhance neuroregeneration of the PN and re-innervation of the EUS, as shown in (C). Unassisted regeneration of the PN results in increase in muscle fibers innervated by a single motor neuron, as shown in (D). With time after unassisted partial regeneration, axons atrophy with aging, as shown in (E).
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