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

项目摘要/摘要 向脊髓横断部位释放BDNF或NT-3神经营养因子的改良成纤维细胞移植物促进 成年脊椎猫足底负重跑台运动的恢复(即使没有体重 支持训练)，通过增加运动中枢区域的活动。与Body-连用- 负重跑步机训练，神经营养素增强训练恢复并能起到作用 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，这具有进一步发展的高风险 脊髓受损。我们的初步数据显示，鞘内神经营养因子进入腰椎 通过植入迷你泵的区域同样有效地促进运动恢复，并导致增加 神经元间放电。虽然这些初步结果是在尖锐的棘化动物身上得出的，但最近的结果是 通过细胞移植物输送神经营养因子表明，将神经营养因子输送到脊髓可以重新 在慢性脊髓损伤模型中激活运动回路，提示鞘内分娩可能 重新激活与脊髓上输入长期隔绝的运动中枢。神经营养因子的选择 重新启动运动回路可能对神经病理性疼痛的发展有影响，这是一种 在临床应用之前需要考虑的重要问题。脑源性神经营养因子和神经营养因子-3在感觉上的不同作用 传入和背角对感觉刺激的反应，有一些相互矛盾的报道。 神经营养因子可增强或减少疼痛反应。确认神经营养因子单独在康复中的作用 确定这两种神经营养因子对脊髓背角神经元的影响也是当务之急。 无害和有害的刺激。 根据我们的初步数据，我们假设鞘内注射神经营养因子(BDNF或NT- 3)将通过以下方式在急性和慢性脊髓损伤模型中促进跑步机负重踏步 以可塑性的方式增加中间带神经元间的活性。我们预测，无论是神经营养素 降低I-II板层神经元与III-V板层神经元对低水平刺激的反应比率(机械刺激 痛觉异常)，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).