Proteoglycan degradation and functional recovery after peripheral nerve injury

描述（由申请人提供）：由于周围神经中受损轴突的再生优于中枢神经系统中受损轴突的再生，因此认为周围神经损伤后的神经再生非常好。然而，只有一小部分周围神经损伤的成年患者会恢复全部功能。这种功能恢复不佳的最常见原因是受损的轴突不能充分再生以恢复功能。使用一种新的技术，在手术修复时，通过应用降解再生轴突环境中生长抑制蛋白聚糖的细菌酶的混合物，可以显著增强切割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。本R21应用程序的目标是开始使用该新技术评价周围神经损伤后的功能恢复。将在坐骨神经横断和手术修复后的大鼠中研究肌肉运动和感觉神经再支配恢复的时间过程和程度以及正常肌肉活动和踝关节运动的恢复。为了评价肌肉神经再支配的时间和程度，将使用长期植入的EMG丝电极记录直接肌肉和H反射活动，以响应损伤部位上方切割和手术修复神经的电刺激。为了评价肌肉功能的恢复，将记录比目鱼肌和内侧腓肠肌的EMG活动，并在平地上的跑步机上行走期间以及上下坡期间监测踝关节运动学。在用软骨素酶ABC、肝素酶I和肝素酶III的混合物处理的大鼠中，将这些功能结果测量值与从神经已被切割和修复但未接受其他处理的一组动物中获得的功能结果测量值进行比较。周围神经损伤后的不良恢复仍然是一个重要的临床问题，并且可能具有阻碍受影响患者寻求治疗的额外不利影响。这项建议旨在评估一种治疗周围神经损伤的技术，如果成功的话，可能会对一个相对较大的治疗不足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.