能量代谢在周围神经损伤修复中的变化及其作用

Peripheral nerve injury (PNI) is very common in clinic. The result of traditional neurorrhaphy which include epineurial neurorrhaphy and perineurial neurorrhaphy method is not satisfied in most cases. The main reasons are: 1, the proximal sensory and motor nerve fibers can not specific generate to the distal end of each. 2, the target organs of muscles have already atrophied before innervated by regeneration nerve fiber. How to accelerate the growth of nerve fibers, and how to improve the distal target organ's function after peripheral nerve injury repaired is still a hot research spot in this field. The previous studies show that the function by using biological conduit small gap sleeve bridging neurorrhaphy is much better than epineurial neurorrphy method in rotated nerve trunk which commonly occurs in clinic cases; and more interesting thing we found that less nerve fibers in proximal side can generate to much more nerve fibers in distal nerve side. This phenomenon was named "multiple regeneration of nerve". The maximal mature nerve fibers regeneration rate can be 3.3 times if the distal end nerve fibers are enough. This new method can play the great role in improving the plasticity, the selective regeneration and the proliferation of the nerve fibers after the injured nerve repaired, and the new neurorrhaphy method also is good for target organ function recovery. After approved by SFDA, the new method has already been proved by multiple center clinical trails. The result showed that the new neurorrhaphy method was better than epineurial neurorrhaphy. So it is possible that one day in the future small gap sleeve bridging neurorrhaphy will replace the old methods which are still used in clinic today. Among the whole procedure, Energy metabolism of the Anterior horn motor neurons of spinal cord, nerve fibers and muscles is also an important factor and component for nerve regeneration. Nerve and muscle are all important energy consumption organs. Plenty energy is needed not only during the nerve fiber end secretion, but also in Excited - contraction coupling under the nerve generation. It is well known that mitochondrion is mainly responsible for energy metabolism including energy mobilize energy accumulation and energy release. And it also should be the most important energy regulon during the procedure of peripheral nerve repair and recovery. So in the recovery of the injured peripheral nerve, does the energy metabolism effect the nerve regeneration and atrophy of distal muscle target organs? What the roles of mitochondria play in that? At present, it is still unclear. So this study will mainly study energy metabolism character, and the related material fundamentals and organelle change; then trying to explore the relationship between the energy metabolism with nerve regeneration; further to reveal the mechanism of nerve recovery and regeneration, to look for a new passageway to improve the final function after peripheral nerve injury.

周围神经损伤在临床中非常常见，传统的神经外膜或束膜缝合修复后其功能恢复效果并不理想。如何促进神经损伤修复后靶器官的功能恢复一直是研究的热点。前期研究证实：生物套管小间隙套接法修复周围神经损伤效果优于临床常见的断端稍有旋转的神经外膜缝合，而近端少量神经纤维可以支配远端较多的神经纤维，故生物套管小间隙套接法具备替代目前临床常用的神经外膜缝合的可行性，并且有利于充分发挥神经的可塑性、再生选择性和倍数再生支配特性，有利于靶器官功能的恢复。在此过程中，神经元及神经纤维的能量代谢即是神经功能状态的一个指标，又是神经再生的重要影响因素，然而神经元及神经纤维的能量代谢到底如何？能量代谢的变化如何影响神经再生？目前仍不清楚。本研究拟通过了解神经再生过程中能量代谢变化及其物质基础，探索能量代谢和神经再生修复的关系，以期进一步揭示周围神经损伤修复的机制及其影响因素并寻求新的促进周围神经损伤修复的切入点。

周围神经损伤是临床上常见的损伤类型之一，其修复后神经恢复的效果不佳，带来严重的经济和社会负担。前期研究证实：小间隙套接法修复周围神经效果优于传统的外膜缝合。但神经修复过程中的神经能量代谢变化及其机制尚不清楚。线粒体是细胞的能量工厂，还是细胞内信号的调节场所，神经修复过程与能量的代谢密切相关，更离不开细胞内各种信号因子的调节。本研究深入研究了周围神经损伤对神经纤维及脊髓前角能量代谢的影响及线粒体生成的调控；并分析了周围神经损伤后线粒体定位的抗氧化剂对神经再生的影响。研究结果显示：大鼠坐骨神经损伤后4周内（单纯切断坐骨神经，不予缝合），近端神经中ATP含量以及线粒体生成的调控因子PGC-1α、TFAM、NRF-1，活性氧(reactive oxygen species, ROS)、线粒体DNA表达量升高，电镜下可见周围神经轴突和雪旺氏细胞中线粒体数目增加；脊髓前角ATP、PGC-1α、TFAM、NRF-1表达量下降，电镜下可见脊髓前角运动神经元中线粒体明显肿胀、变性。小间隙套接法修复坐骨神经后，可以观察到相同的变化趋势。在坐骨神经修复后予以线粒体定位的抗氧化剂SS31治疗，可以发现术后3天至28天，断端神经ATP、PGC-1α、TFAM、NRF-1、ROS表达量下降；术后10周，SS31干预组的肌肉萎缩恢复、神经电生理的神经传导速度、轴突修复优于对照组，周围神经修复程度明显优于对照组。.本课题研究了周围神经损伤过程中能量代谢的变化以及对线粒体生成的调控，并发现抗氧化剂可以调节神经的能量代谢从而来提高神经修复效果，可能为临床保护神经元、促进周围神经再生提供新的治疗方向。