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

Temple Univ Of The Commonwealth, Philadelphia PA

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Linked publications & trials

Abstract

Differential effects of BDNF and NT-3 on locomotor recovery and sensory response 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. Used in combination with body-weight supported treadmill training, they 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 with limited risks and side effects. 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 be efficacious for chronic injury. 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. 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).