Proteoglycan degradation and functional recovery after peripheral nerve injury

描述（申请人提供）：由于周围神经受损轴突的再生比中枢神经系统的轴突好，所以假设周围神经损伤后的神经再生是优秀的。然而，只有一小部分周围神经损伤的成年患者能完全恢复功能。这种功能恢复不良的最常见原因是受损的轴突不能充分再生以恢复功能。利用一项新技术，在手术修复时，应用一种细菌酶的混合物，在再生的轴突环境中降解生长抑制蛋白聚糖，可以显著增强周围神经切割轴突的早期再生。这种早期轴突再生的增强是否会转化为肌肉神经再生和功能恢复的增强尚不清楚。这项R21应用的目的是开始评估周围神经损伤后使用这种新技术的功能恢复。我们将在大鼠坐骨神经横断和手术修复后研究肌肉运动和感觉神经支配恢复的时间和程度，以及正常肌肉活动和踝关节运动的恢复。为了评估肌肉再神经支配的时间和程度，将使用长期植入的肌电图丝电极记录直接肌肉和h反射活动对损伤部位上方切割和手术修复的神经的电刺激。为了评估肌肉功能的恢复情况，将记录比目鱼肌和腓肠肌内侧肌的肌电图活动，并监测在平地和上下台阶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，这些功能结果将与神经被切断和修复但未接受其他治疗的一组动物的结果进行比较。周围神经损伤后的不良恢复仍然是一个重要的临床问题，并可能有额外的不利影响，使患者不愿寻求治疗。本提案旨在评估一种治疗周围神经损伤的医学技术，如果成功，可能对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.