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

项目总结/摘要 将BDNF或NT-3神经营养因子释放到脊髓横断部位的修饰的成纤维细胞移植物促进了脊髓横断部位的生长。 成年脊髓猫足底负重踏车运动的恢复（即使没有体重 支持训练）通过增加运动中心区域的活动。与身体结合使用- 重量支持的跑步机训练，神经营养因子增加恢复与训练，可以服务于 作为跑步机训练和硬膜外刺激的康复补充。目前的交付方式 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。 脊髓损伤我们的初步数据表明，鞘内输送神经营养素到腰椎， 通过植入的微型泵的区域在促进运动恢复方面同样有效， 神经元间放电虽然这些初步结果是在急性脊髓动物，最近的结果与 通过细胞移植物递送神经营养因子显示，神经营养因子向脊髓的递送可以重新激活神经营养因子。 参与慢性脊髓损伤模型的运动回路，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。神经营养素的选择 重新启动运动回路可能对神经性疼痛的发展有影响， 在临床应用之前需要考虑的重要问题。BDNF和NT-3对感觉神经元的作用不同， 传入神经和背角对感觉刺激的反应，有一些相互矛盾的报告， 神经营养素增强或减少疼痛反应。证实神经营养因子单独在恢复中的作用 是必要的，因为这是建立两种神经营养因子对背角神经元的反应的影响， 无害和有害的刺激。 基于我们的初步数据，我们假设鞘内递送神经营养因子（BDNF或NT-1）， 3)在急性和慢性脊髓损伤模型中， 以可塑性方式增加中间区神经元间的活动。我们预测神经营养因子 降低响应于低水平刺激（机械刺激）的板层I-II神经元与板层III-V神经元的比率 异常性疼痛），但BDNF将导致板层I-II神经元对高水平刺激的反应明显增加 （有害刺激）。

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).