Proteoglycan degradation and functional recovery after peripheral nerve injury

描述(申请人提供)：由于周围神经损伤的轴突比中枢神经系统的轴突再生更好，因此认为周围神经损伤后的神经再生是非常好的。然而，只有一小部分周围神经损伤的成年患者会恢复完全功能。造成这种功能恢复不良的最常见的原因是，受损的轴突再生不足，无法恢复功能。利用一项新技术，在手术修复时，通过在再生轴突环境中应用一种能降解生长抑制蛋白多糖的细菌酶混合物，可以显著促进切断的周围神经中轴突的早期再生。这种早期轴突再生的增强是否会转化为肌肉神经再支配和功能恢复的增强尚不清楚。这项R21应用的目标是开始使用这项新技术评估周围神经损伤后的功能恢复。在大鼠坐骨神经切断和手术修复后，将研究肌肉运动和感觉神经的恢复以及正常肌肉活动和踝关节运动恢复的时间过程和程度。为了评估肌肉再神经支配的时间和程度，将使用长期植入的EMG丝电极记录直接肌肉和H反射活动，以响应对损伤部位上方被切断和手术修复的神经的电刺激。为了评估肌肉功能的恢复，将记录比目鱼肌和腓肠肌内侧的肌电活动，并监测在平地和上下坡度的跑步机上行走时的踝关节运动学。在用软骨素酶ABC、肝素酶I和肝素酶III混合治疗的大鼠中，这些功能结果指标将与一组动物的结果进行比较，这些动物的神经被切断和修复，但没有接受其他治疗。周围神经损伤后恢复不佳仍然是一个重要的临床问题，可能会产生额外的不利影响，阻碍受影响的患者寻求治疗。这项提案旨在评估一种治疗周围神经损伤的医疗技术，如果成功，可能会对相对较大的未得到充分治疗的患者群体产生重要影响。

DESCRIPTION (provided by applicant): Because damaged axons in peripheral nerves regenerate better than those in the central nervous system, it is assumed that nerve regeneration after peripheral nerve injuries is excellent. However, only a small fraction of adult patients with peripheral nerve injuries will regain full function. The reason most often given for this poor functional recovery is that damaged axons do not regenerate sufficiently to restore function. Using a novel technology, the early regeneration of axons in cut peripheral nerves can be enhanced significantly by the application, at the time of surgical repair, of a mixture of bacterial enzymes which degrade growth inhibitory proteoglycans in the environment of the regenerating axons. Whether this enhancement of early axon regeneration will translate to an enhancement of muscle reinnervation and functional recovery is not known. The goal of this R21 application is to begin to evaluate functional recovery after peripheral nerve injury using this new technology. The time course and extent of restitution of motor and sensory reinnervation of muscles and the recovery of normal muscle activity and ankle joint movements will be studied in rats after transection and surgical repair of the sciatic nerve. To evaluate the timing and extent of reinnervation of muscles, direct muscle and H-reflex activity will be recorded using chronically implanted EMG wire electrodes in response to electrical stimulation of the cut and surgically repaired nerve above the lesion site. To evaluate the return of muscle function, EMG activity will be recorded from the soleus and medial gastrocnemius muscles and ankle joint kinematics will be monitored during walking on a treadmill on level ground and both up and down grades. In rats treated with a mixture of chondroitinase ABC, heparinase I, and heparinase III, these functional outcome measures will be compared to those obtained from a group of animals whose nerves have been cut and repaired but who received no other treatments. The poor recovery following peripheral nerve injuries remains an important clinical problem and may have the added untoward effect of discouraging treatment seeking by affected patients. This proposal seeks to evaluate a technology for medical treatment of peripheral nerve injuries which, if successful, could have an important impact on a relatively large group of under-treated patients.