Intrathecal pump delivery of neurotrophins for locomotor recovery after spinal cord injury

鞘内泵输送神经营养素用于脊髓损伤后的运动恢复

基本信息

批准号：
10386761
负责人：
Michel A Lemay
金额：
$ 34.23万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386761
关键词：
Acute Adult Afferent Neurons Animal Model Animals Area Autologous Body Weight Brain-Derived Neurotrophic Factor Caliber Cell Transplantation Cells Cerebrospinal Fluid Chest Chronic Clinical Complement Conflict (Psychology)Data Development Dose Exercise Feedback Felis catus Fiber Fibroblasts Functional disorder Hindlimb Human Hypersensitivity Implant Individual Infusion procedures Injury Interneurons Locomotion Locomotor Recovery Lumbar spinal cord structure Measures Methods Modeling Motor Activity Neurons Neurotrophin 3 Nociception Pain Pattern Perception Posterior Horn Cells Pump Recovery Rehabilitation therapy Reporting Response Latencies Risk Role Sensory Site Spinal Spinal Cord Spinal Injuries Spinal cord injury Stimulus Synapses Testing Thermal Hyperalgesias Time Training Training Support Transplantation Weight-Bearing state Withdrawal Work Xenograft procedure afferent nerve allodynia base behavior test central pain chronic pain clinical application dorsal horn experimental study heat stimulus high risk implantation injured mechanical allodynia neurotrophic factor pain reduction painful neuropathy programs response sensory stimulus side effect spinal reflex treadmill treadmill training

项目摘要

Project Summary/Abstract Modified fibroblast grafts releasing BDNF or NT-3 neurotrophins into the spinal transection site promote the recovery of plantar weight-bearing treadmill locomotion in adult spinal cats (even without body-weight supported training) by increasing the activity of the locomotor center region. Used in combination with body- weight supported treadmill training, neurotrophins augment the recovery obtained with training and could serve as a rehabilitative supplement to treadmill training and epidural stimulation. The current delivery method requires exposing the spinal cord and inserting the cells into the injury site which carries high risks of further damage to the spinal cord. Our preliminary data show that intrathecal delivery of neurotrophins to the lumbar area via an implanted mini-pump is just as efficacious at promoting locomotor recovery and leads to increased interneuronal firing. While these preliminary results are in acutely spinalized animals, recent results with delivery of neurotrophins via cellular grafts show that delivery of neurotrophins to the spinal cord can re- engage the locomotor circuitry in chronic spinal cord injury models, suggesting that intrathecal delivery might re-activate locomotor centers chronically isolated from supraspinal inputs. The choice of neurotrophin used to re-engage the locomotor circuitry may have implications for the development of neuropathic pain, which is a significant issue to consider prior to clinical applications. BDNF and NT-3 have different actions on sensory afferents and dorsal horn’s response to sensory stimuli, with a number of conflicting reports on whether the neurotrophins enhance or reduce pain responses. Confirming the role of either neurotrophin alone in recovery is imperative, as is establishing the effects of both neurotrophins on dorsal horn neurons’ responses to innocuous and noxious stimuli. Based on our preliminary data we hypothesize that intrathecal delivery of either neurotrophin (BDNF or NT- 3) will promote treadmill weight-bearing stepping in both acute and chronic models of spinal cord injury by increasing intermediate zone interneuronal activity in a plastic manner. We predict that either neurotrophin will reduce the ratio of laminae I-II neurons to laminae III-V neurons responsive to low level stimuli (mechanical allodynia), but that BDNF will lead to a clear increase in laminae I-II neurons’ response to high-level stimuli (noxious stimuli).

项目概要/摘要修饰的成纤维细胞移植物将 BDNF 或 NT-3 神经营养因子释放到脊柱横断部位，促进成年脊椎猫恢复足底负重跑步机运动（即使没有体重通过增加运动中心区域的活动来支持训练）与身体结合使用。重量支持的跑步机训练，神经营养因子可以增强训练后的恢复效果，并可以发挥作用作为跑步机训练和硬膜外刺激的康复补充。需要暴露脊髓并将细胞插入损伤部位，这具有进一步损伤的高风险我们的初步数据表明，神经营养因子鞘内输送至腰椎。通过植入微型泵的区域在促进运动恢复方面同样有效，并导致增加虽然这些初步结果是在急性脊髓动物中进行的，但最近的结果是通过细胞移植物输送神经营养素表明，将神经营养素输送到脊髓可以重新参与慢性脊髓损伤模型中的运动回路，表明鞘内给药可能重新激活长期与脊髓上输入隔离的运动中枢选择神经营养蛋白用于。重新参与运动回路可能会对神经性疼痛的发展产生影响，这是一种临床应用前需要考虑的重要问题是 BDNF 和 NT-3 对感觉有不同的作用。传入神经和背角对感觉刺激的反应，关于传入神经和背角是否对感觉刺激做出反应，有许多相互矛盾的报告证实神经营养因子单独在恢复中的作用。势在必行，就像确定两种神经营养素对背角神经元的反应的影响一样无害和有害的刺激。根据我们的初步数据，我们追求鞘内递送神经营养素（BDNF 或 NT- 3）将促进急性和慢性脊髓损伤模型中的跑步机负重行走我们预测任一神经营养素都会以可塑的方式增加中间区神经元活动。降低响应低水平刺激（机械刺激）的 I-II 层神经元与 III-V 层神经元的比例异常性疼痛），但 BDNF 会导致 I-II 层神经元对高水平刺激的反应明显增加（有害刺激）。