Hart A M, Terenghi G, Kellerth J-O, Wiberg M
Blond-McIndoe Research Laboratories, The University of Manchester, Stopford Building, Room 3.102, Oxford Road, Manchester M13 9PT, UK.
Neuroscience. 2004;125(1):91-101. doi: 10.1016/j.neuroscience.2003.12.040.
Neuronal death is a major factor in many neuropathologies, particularly traumatic, and yet no neuroprotective therapies are currently available clinically, although antioxidants and mitochondrial protection appear to be fruitful avenues of research. The simplest system involving neuronal death is that of the dorsal root ganglion after peripheral nerve trauma, where the loss of approximately 40% of primary sensory neurons is a major factor in the overwhelmingly poor clinical outcome of the several million nerve injuries that occur each year worldwide. N-acetyl-cysteine (NAC) is a glutathione substrate which is neuroprotective in a variety of in vitro models of neuronal death, and which may enhance mitochondrial protection. Using TdT uptake nick-end labelling (TUNEL), optical disection, and morphological studies, the effect of systemic NAC treatment upon L4 and 5 primary sensory neuronal death after sciatic nerve transection was investigated. NAC (150 mg/kg/day) almost totally eliminated the extensive neuronal loss found in controls both 2 weeks (no treatment 21% loss, NAC 3%, P=0.03) and 2 months after axotomy (no treatment 35% loss, NAC 3%, P=0.002). Glial cell death was reduced (mean number TUNEL positive cells 2 months after axotomy: no treatment 51/ganglion pair, NAC 16/ganglion pair), and mitochondrial architecture was preserved. The effects were less profound when a lower dose was examined (30 mg/kg/day), although significant neuroprotection still occurred. This provides evidence of the importance of mitochondrial dysregulation in axotomy-induced neuronal death in the peripheral nervous system, and suggests that NAC merits investigation in CNS trauma. NAC is already in widespread clinical use for applications outside the nervous system; it therefore has immediate clinical potential in the prevention of primary sensory neuronal death, and has therapeutic potential in other neuropathological systems.
神经元死亡是许多神经病理学中的一个主要因素，尤其是在创伤性神经病变中。然而，目前临床上尚无神经保护疗法，尽管抗氧化剂和线粒体保护似乎是富有成效的研究途径。涉及神经元死亡的最简单系统是外周神经损伤后背根神经节的系统，每年全球发生数百万例神经损伤，其中约40%的初级感觉神经元丧失是导致临床结果极其糟糕的一个主要因素。N-乙酰半胱氨酸（NAC）是一种谷胱甘肽底物，在多种神经元死亡的体外模型中具有神经保护作用，并且可能增强线粒体保护。利用末端脱氧核苷酸转移酶介导的缺口末端标记法（TUNEL）、光学解剖和形态学研究，研究了全身应用NAC治疗对坐骨神经横断后L4和L5初级感觉神经元死亡的影响。NAC（150毫克/千克/天）几乎完全消除了对照组在轴突切断后2周（未治疗组损失21%，NAC组损失3%，P=0.03）和2个月时（未治疗组损失35%，NAC组损失3%，P=0.002）出现的广泛神经元损失。神经胶质细胞死亡减少（轴突切断后2个月TUNEL阳性细胞平均数：未治疗组为51个/神经节对，NAC组为16个/神经节对），线粒体结构得以保留。当检测较低剂量（30毫克/千克/天）时，效果不太显著，尽管仍有显著的神经保护作用。这为线粒体调节异常在周围神经系统轴突切断诱导的神经元死亡中的重要性提供了证据，并表明NAC在中枢神经系统创伤中值得研究。NAC已在神经系统以外的领域广泛应用于临床；因此，它在预防初级感觉神经元死亡方面具有直接的临床潜力，并且在其他神经病理系统中具有治疗潜力。
