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).
The proposed experiments aim to develop, validate and explore the effects on lumbar locomotor center activity of a clinically translational method of neurotrophin delivery to the lumbar cord that restores stepping ability in a large mammalian model of spinal cord injury. The proposal will also explore the potential side effects of these neurotrophins on the development of sensory dysfunction such as neuropathic pain.
