Hart Andrew M, Terenghi Giorgio, Wiberg Mikael
Blond-McIndoe Research Laboratories, Plastic and Reconstructive Surgery Research, The University of Manchester, Stopford Building, Room 3.102, Oxford Road, Manchester M13 9PT, UK.
Neurol Res. 2008 Dec;30(10):999-1011. doi: 10.1179/174313208X362479.
Despite considerable microsurgical innovation in peripheral nerve repair, the outcome has improved little since the 1940s, reflecting surgical inability to adequately address the complex neurobiology of nerve injury and regeneration. Axotomy-induced neuronal death is potentially the most fundamental problem, and given recently published data, a review is timely.
Initial review of relevant doctoral theses from the University of Umeå, and Blond-McIndoe Research Laboratories, the University of Manchester, plus initial PubMed search including terms 'neuron death' and 'neuroprotection', subsequently expanded to relevant quoted articles.
Various factors related to patient (principally age) and injury (Sunderland grade, proximity to cell body and mechanism) determine the extent of neuronal death, the mechanism of which is reviewed. A considerable proportion of sensory neurons (particularly small cutaneous afferents) die after distal injury and death is more widespread after proximal injury. Motor neurons are susceptible to post-ganglionic plexus and spinal root level injury. Root avulsion causes the greatest cell death. The time course of neuronal death is fortuitously slow and mainly occurs by a process akin to apoptosis. A therapeutic window therefore exists, as do potential neuroprotective targets. Nerve repair is partly neuroprotective, but must be performed early. Exogenous neurotrophic factor administration (e.g. in tissue engineered conduits) is beneficial, but not practical for various reasons. In contrast, adjuvant neuroprotective pharmacotherapy is practical, and two clinically safe agents are reviewed. Acetyl-L-carnitine arrests sensory neuronal death and speeds up regeneration. N-acetyl-cysteine provides comparable sensory neuronal protection via mitochondrial preservation and protects motor neurons. Both agents are well characterized experimentally and highly effective even after clinically relevant delays between injury and treatment. Barriers to translational research are being addressed.
The future of peripheral nerve repair lies in modulating neurobiology at the time of injury, repair and during regeneration. Neuroprotection may be an essential component of that therapeutic package.
尽管周围神经修复在显微外科方面有了相当大的创新，但自20世纪40年代以来，治疗效果改善甚微，这反映出手术无法充分应对神经损伤和再生的复杂神经生物学问题。轴突切断术导致的神经元死亡可能是最根本的问题，鉴于最近发表的数据，进行一次综述很有必要。
初步查阅于默奥大学以及曼彻斯特大学的布朗德 - 麦金杜研究实验室的相关博士论文，并在PubMed上进行初步检索，检索词包括“神经元死亡”和“神经保护”，随后扩展到相关引用文章。
与患者（主要是年龄）和损伤（桑德兰分级、与细胞体的距离和机制）相关的各种因素决定了神经元死亡的程度，并对其机制进行了综述。相当一部分感觉神经元（尤其是小的皮肤传入神经元）在远端损伤后死亡，近端损伤后死亡更为广泛。运动神经元易受节后神经丛和脊髓神经根水平损伤的影响。神经根撕脱导致的细胞死亡最多。神经元死亡的时间进程幸运地较为缓慢，主要通过类似于凋亡的过程发生。因此存在一个治疗窗口，也有潜在的神经保护靶点。神经修复在一定程度上具有神经保护作用，但必须尽早进行。给予外源性神经营养因子（如在组织工程导管中）是有益的，但由于各种原因并不实用。相比之下，辅助性神经保护药物治疗是可行的，并对两种临床安全的药物进行了综述。乙酰 - L - 肉碱可阻止感觉神经元死亡并加速再生。N - 乙酰半胱氨酸通过保护线粒体提供类似的感觉神经元保护，并保护运动神经元。这两种药物在实验中都有充分的特征描述，即使在损伤和治疗之间出现临床相关延迟后也非常有效。正在解决转化研究的障碍。
周围神经修复的未来在于在损伤、修复和再生期间调节神经生物学。神经保护可能是该治疗方案的重要组成部分。
