Kathe Claudia, Hutson Thomas Haynes, McMahon Stephen Brendan, Moon Lawrence David Falcon
Neurorestoration Department, Wolfson Centre for Age-Related Diseases, King's College London, University of London, London, United Kingdom.
Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
Elife. 2016 Oct 19;5:e18146. doi: 10.7554/eLife.18146.
Brain and spinal injury reduce mobility and often impair sensorimotor processing in the spinal cord leading to spasticity. Here, we establish that complete transection of corticospinal pathways in the pyramids impairs locomotion and leads to increased spasms and excessive mono- and polysynaptic low threshold spinal reflexes in rats. Treatment of affected forelimb muscles with an adeno-associated viral vector (AAV) encoding human Neurotrophin-3 at a clinically-feasible time-point after injury reduced spasticity. Neurotrophin-3 normalized the short latency Hoffmann reflex to a treated hand muscle as well as low threshold polysynaptic spinal reflexes involving afferents from other treated muscles. Neurotrophin-3 also enhanced locomotor recovery. Furthermore, the balance of inhibitory and excitatory boutons in the spinal cord and the level of an ion co-transporter in motor neuron membranes required for normal reflexes were normalized. Our findings pave the way for Neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms.
脑和脊髓损伤会降低活动能力，并常常损害脊髓中的感觉运动处理，导致痉挛。在此，我们证实，锥体中皮质脊髓通路的完全横断会损害运动，并导致大鼠痉挛增加以及单突触和多突触低阈值脊髓反射过度。在损伤后的临床可行时间点，用编码人神经营养因子-3的腺相关病毒载体（AAV）治疗受影响的前肢肌肉可减轻痉挛。神经营养因子-3使治疗的手部肌肉的短潜伏期霍夫曼反射以及涉及其他治疗肌肉传入神经的低阈值多突触脊髓反射恢复正常。神经营养因子-3还促进了运动恢复。此外，脊髓中抑制性和兴奋性终扣的平衡以及正常反射所需的运动神经元膜中离子共转运体的水平也恢复了正常。我们的研究结果为将神经营养因子-3作为一种治疗痉挛根本原因而非仅治疗其症状的疗法铺平了道路。
