Beattie Michael S, Hermann Gerlinda E, Rogers Richard C, Bresnahan Jacqueline C
Department of Neuroscience, The Ohio State University Medical Center, 333 W. 10th Avenue, Columbus, OH 43210, USA.
Prog Brain Res. 2002;137:37-47. doi: 10.1016/s0079-6123(02)37006-7.
Current treatments for acute spinal cord injury are based on animal models of human spinal cord injury (SCI). These models have shown that the initial traumatic injury to cord tissue is followed by a long period of secondary injury that includes a number of cellular and biochemical cascades. These secondary injury processes are potential targets for therapies. Continued refinement of rat and mouse models of SCI, along with more detailed analyses of the biology of the lesion in these models, points to both necrotic and apoptotic mechanisms of cell death after SCI. In this chapter, we review recent evidence for long-term apoptotic death of oligodendrocytes in long tracts undergoing Wallerian degeneration following SCI. This process appears to be related closely to activation of microglial cells. It is has been thought that microglial cells might be the source of cytotoxic cytokines, such as tumor necrosis factor-alpha (TNF-alpha), that kill oligodendrocytes. However, more recent evidence in vivo suggests that TNF-alpha by itself may not induce necrosis or apoptosis in oligodendrocytes. We review data that suggests other possible pathways for apoptosis, such as the neurotrophin receptor p75 which is expressed in both neurons and oligodendrocytes after SCI in rats and mice. In addition, it appears that microglial activation and TNF-alpha may be important in acute SCI. Ninety minutes after a moderate contusion lesion, microglia are activated and surround dying neurons. In an 'atraumatic' model of SCI, we have now shown that TNF-alpha appears to greatly potentiate cell death mediated by glutamate receptors. These studies emphasize that multiple mechanisms and interactions contribute to secondary injury after SCI. Continued study of both contusion models and other new approaches to studying these mechanisms will be needed to maximize strategies for acute and chronic therapies, and for neural repair.
目前针对急性脊髓损伤的治疗方法是基于人类脊髓损伤（SCI）的动物模型。这些模型表明，脊髓组织最初的创伤性损伤之后会有一段很长的继发性损伤期，其中包括许多细胞和生化级联反应。这些继发性损伤过程是治疗的潜在靶点。对大鼠和小鼠SCI模型的不断完善，以及对这些模型中损伤生物学的更详细分析，揭示了SCI后细胞死亡的坏死和凋亡机制。在本章中，我们回顾了近期关于SCI后长束中少突胶质细胞长期凋亡死亡的证据。这一过程似乎与小胶质细胞的激活密切相关。人们一直认为小胶质细胞可能是细胞毒性细胞因子（如肿瘤坏死因子-α，TNF-α）的来源，这些细胞因子会杀死少突胶质细胞。然而，最近体内实验的证据表明，TNF-α本身可能不会诱导少突胶质细胞坏死或凋亡。我们回顾了一些数据，这些数据提示了其他可能的凋亡途径，比如神经营养因子受体p75，在大鼠和小鼠SCI后，神经元和少突胶质细胞中均有表达。此外，小胶质细胞激活和TNF-α在急性SCI中似乎也很重要。中度挫伤性损伤90分钟后，小胶质细胞被激活并包围垂死的神经元。在一个SCI的“无创伤”模型中，我们现在已经表明，TNF-α似乎极大地增强了由谷氨酸受体介导的细胞死亡。这些研究强调，多种机制和相互作用促成了SCI后的继发性损伤。需要持续研究挫伤模型以及研究这些机制的其他新方法，以最大限度地制定急性和慢性治疗策略以及神经修复策略。
