Electrical Stimulation Facilitation of Recovery from Childbirth Injury

说明： 尿失禁，特别是压力性尿失禁(SUI)，在女退伍军人中很常见，也非常令人烦恼。虽然不会危及生命，但SUI极大地降低了生活质量，在女性退伍军人中，SUI与抑郁症和性侵犯史显著相关。隋症也与阴道分娩有很强的相关性，这可能会对 盆底的肌肉和器官，包括外括约肌(EUS)。此外，支配EUS的阴部神经在分娩过程中可在Alcock管中损伤，位于其尿路神经的近端。因此，分娩期间发生的损伤代表了一种独特的神经肌肉损伤：靶肌肉(EUS)及其神经同时受到损伤。这两种损伤，以及盆底组织和肌肉的损伤与SUI的后期发展密切相关。周围神经损伤后，脑源性神经营养因子(BDNF)必须由靶肌肉产生，以再生运动神经元并重新支配肌肉。然而，如果肌肉受损，BDNF会抑制神经肌肉接头(NMJ)的修复。因此，当神经及其支配的肌肉都受到损伤时，就像分娩时可能发生的那样，肌肉对脑源性神经营养因子的下调会抑制神经再生。我们开发了一种新的模拟分娩损伤的动物模型，并证明了神经营养素介导的机制可能是阴道分娩后神经再生延迟和可能不完全的原因。电刺激(e-stim)增加受损神经元中BDNF的表达，促进神经再生。它可能是一种比BDNF治疗并发症更少的替代疗法。促进神经再生的E-stim疗法取得了好坏参半的结果，部分原因是它只在神经损伤后使用，而不是像分娩时那样在神经和肌肉联合损伤后使用。正因为如此，在特定的临床相关模型中研究e-stim在神经和肌肉组合损伤后的作用机制对于优化治疗和患者亚群治疗至关重要。我们最近的数据表明，模拟分娩损伤后刺激阴部神经可以上调阴部神经细胞中的BDNF，促进尿路功能的恢复。然而，这些数据是相关的，而不是因果关系。因此，在这个项目中要检验的假设是，e-stim可以促进恢复 通过脑源性神经营养因子介导的机制防止模拟分娩损伤。这一假设将通过以下具体目标(SO)进行检验：SO1。优化e-stim范式，改善模拟分娩损伤后的康复；二氧化硫。证明使用e-stim加速功能恢复与慢性改善相关；证明BDNF对于阴部神经卡压(PNC)后的自然恢复和模拟分娩损伤后补充BDNF的加速恢复是必要和充分的。SO4.证明e-stim通过BDNF介导的机制促进模拟分娩损伤的康复。该项目将提供关键的临床前数据，以启动临床试验，以评估e-stim对患有SUI的女性退伍军人的康复辅助作用。大约1/3的妇女在分娩后有产后SUI。虽然这在大多数女性中都得到了解决，但这些女性中几乎有一半在5年后会再发，超过一半会在几年后再发，这表明产后SUI预示着以后的SUI。产后SUI的妇女可以组成e-stim的临床试验人群，这种药物可以治疗她们目前的尿失禁，甚至可以预防SUI的再发展。这项研究直接关系到老龄康复研发优先领域。此外，妇女是退伍军人人口中增长最快的部分，占现役部队的14%和新兵的20%，是退伍军人研究计划的优先事项。由于女性退伍军人中大小便失禁和抑郁的关系如此密切，大小便失禁症状的改善可能有助于从抑郁中恢复。

DESCRIPTION: Urinary incontinence, particularly stress urinary incontinence (SUI), is common and very bothersome among female veterans. Although not life threatening, SUI greatly reduces quality of life and, among female veterans is significantly correlated with a history of depression and sexual assault. SUI is also strongly correlated with vaginal delivery of children, which can injure the muscles, and organs of the pelvic floor, including the external urethral sphincter (EUS). In addition, the pudendal nerve, which innervates the EUS, can be injured in Alcock's canal during delivery, proximal to its innervations of the urethra. Thus, the injuries incurred during childbirt represent a unique neuromuscular injury: one in which both the target muscle (the EUS) and its innervation are injured simultaneously. These two injuries, along with injuries to the tissues and muscles of the pelvic floor are strongly correlated with later development of SUI. Brain-derived neurotrophic factor (BDNF) must be produced by the target muscle to regenerate motoneurons and reinnervate the muscle after peripheral nerve injury. However, if muscle is injured, BDNF inhibits neuromuscular junction (NMJ) repair. Therefore, when both a nerve and its innervated muscle are injured, as can occur during childbirth, BDNF downregulation by the muscle inhibits nerve regeneration. We have developed a novel animal model of simulated childbirth injury and have demonstrated that a neurotrophin- mediated mechanism could be responsible for delayed and possibly incomplete neuroregeneration after vaginal delivery. Electrical stimulation (e-stim) increases BDNF expression in injured neurons and promotes nerve regeneration. It may present an alternative therapy with fewer complications than treatment with BDNF. E-stim therapy to promote nerve regeneration has had mixed success, in part because it has only been utilized after nerve injury, not after a combination nerve and muscle injury, as can occur in childbirth. Precisely because of this, investigation of the mechanism of action of e-stim after a combinatorial nerve and muscle injury in a specific clinically related model is crucial for optimizing the therapy and the patient subpopulation to treat. We have recent data that e-stim of the pudendal nerve after simulated childbirth injury upregulates BDNF in pudendal nerve cells and promotes functional recovery of the urethra. However, this data is correlative rather than causative. Therefore, the hypothesis to be tested in this project is that e- stim improves recovery from simulated childbirth injury via a BDNF-mediated mechanism. This hypothesis will be tested via the following specific objectives (SO): SO1. Optimize an e-stim paradigm for improvement of recovery after simulated childbirth injury; SO2. Demonstrate that accelerated recovery of function with e- stim correlates with chronic improvement; SO3. Demonstrate that BDNF is necessary and sufficient for spontaneous recovery after pudendal nerve crush (PNC) and accelerated recovery with supplemental BDNF after simulated childbirth injury. SO4. Demonstrate that e-stim facilitates recovery from simulated childbirth injury via a BDNF-mediated mechanism. This project will provide critical pre-clinical data to initiate a clinical tril to assess e-stim as an adjuvant to rehabilitation for female veterans with SUI. Approximately 1/3 of women have postpartum SUI following delivery. Although this resolves in most women, almost half of these women redevelop it 5 years later and over half redevelop it years later, indicating that postpartum SUI is predictive of later SUI. Women with postpartum SUI could constitute the population for a clinical trial of e- stim, which could treat their current incontinence and preven redevelopment of SUI. This research directly relates to the Rehabilitation R&D Priority Area of Aging. In addition, women are the fastest growing segment of the veteran population, representing 14% of active duty forces and 20% of new military recruits, and are a priority for the VA research program. Since incontinence and depression are so closely correlated among female veterans, improvement of incontinence symptoms may help lead to recovery from depression.