Institute of Neuropathology, University Medical Centre, Gottingen, Germany.
Curr Opin Neurol. 2011 Jun;24(3):224-9. doi: 10.1097/WCO.0b013e328346056f.
Multiple sclerosis (MS) treatments targeting the inflammatory nature of the disease have become increasingly effective in recent years. However, our efforts at targeting the progressive disease phase have so far been largely unsuccessful. This has led to the hypothesis that disease mechanisms independent of an adaptive immune response contribute to disease progression and closely resemble neurodegeneration.
Nonfocal, diffuse changes in the MS brain, especially axonal loss and mitochondrial dysfunction, prove better correlates of disability than total lesion load and have been associated with disease progression. Molecular changes in nondemyelinated MS tissue also suggest that alterations in the MS brain are widespread and consist of pro-inflammatory as well as anti-inflammatory responses. However, local lymphocytic inflammation and microglial activation are salient features of the chronic disease, and T-cell-mediated inflammation contributes to tissue damage. In addition, neuroaxonal cytoskeletal alterations have been associated with disease progression.
Our knowledge of the molecular mechanisms leading to neuroaxonal damage and demise in MS is steadily increasing. Experimental therapies targeting neuroaxonal ionic imbalances and energy metabolism in part show promising results. A better understanding of the molecular mechanisms underlying chronic progression will substantially aid the development of new treatment strategies.
近年来，针对多发性硬化症（MS）炎症本质的治疗方法已越来越有效。然而，我们在针对进行性疾病阶段的努力迄今为止基本上没有成功。这导致了这样一种假设，即独立于适应性免疫反应的疾病机制有助于疾病进展，并且与神经退行性变非常相似。
MS 大脑中非局灶性、弥漫性变化，尤其是轴突丢失和线粒体功能障碍，与残疾的相关性优于总病变负荷，并且与疾病进展相关。非脱髓鞘 MS 组织中的分子变化也表明，MS 大脑中的改变广泛存在，包括促炎和抗炎反应。然而，局部淋巴细胞炎症和小胶质细胞激活是慢性疾病的显著特征，T 细胞介导的炎症会导致组织损伤。此外，神经轴突细胞骨架改变与疾病进展有关。
我们对导致 MS 中神经轴突损伤和死亡的分子机制的了解正在稳步增加。针对神经轴突离子失衡和能量代谢的实验性治疗方法在一定程度上显示出有希望的结果。更好地了解慢性进展的分子机制将极大地帮助开发新的治疗策略。
