Cuthill Daniel J, Fowler Jill H, McCulloch James, Dewar Deborah
Division of Clinical Neuroscience, University of Glasgow, Glasgow, UK.
Exp Neurol. 2006 Aug;200(2):509-20. doi: 10.1016/j.expneurol.2006.03.021. Epub 2006 May 12.
White matter damage occurs following stroke and traumatic brain injury. In preclinical studies of potential therapies to reduce acute brain damage, it is important not only to understand the mechanisms by which this damage occurs, but also to employ techniques that fully quantify the extent of damage. In both respects, neurons have previously received greater attention than axons. The aim of the present study was to compare the extent of axonal damage visualised with different immunohistochemical markers following intracerebral injection of either the excitotoxin AMPA or the mitochondrial inhibitor malonate. Adult mice received intrastriatal injection of toxin and 24 h later the amount of white matter damage visualised with either amyloid precursor protein (APP) or neurofilament 200 (NF200) immunohistochemistry. Malonate induced a dose-dependent increase in the extent of axonal damage with either marker. However, AMPA induced a dose-dependent increase in the extent of axonal damage visualised by NF200 immunoreactivity but not by APP immunoreactivity. Malonate and AMPA also differed in their effects on other assessments of white matter integrity and (14)C-2-deoxyglucose autoradiography revealed the two toxins to differ in their initial effects on cerebral metabolism. These data indicate that the ability of commonly-used axonal damage markers to quantify the full extent of white matter damage differs following initial excitotoxicity or mitochondrial inhibition. We also confirmed that the markers reveal different extents of axonal damage in a rat model of focal cerebral ischaemia. Therefore, in preclinical studies designed to assess brain protecting agents, it is advisable to use more than one marker to quantify the true extent of axonal damage.
白质损伤发生在中风和创伤性脑损伤之后。在减少急性脑损伤的潜在疗法的临床前研究中，不仅要了解这种损伤发生的机制，而且要采用能够充分量化损伤程度的技术，这一点很重要。在这两个方面，神经元此前受到的关注比轴突更多。本研究的目的是比较在脑内注射兴奋性毒素AMPA或线粒体抑制剂丙二酸后，用不同免疫组化标记物可视化的轴突损伤程度。成年小鼠接受纹状体内毒素注射，24小时后用淀粉样前体蛋白（APP）或神经丝200（NF200）免疫组化观察白质损伤量。丙二酸使两种标记物的轴突损伤程度呈剂量依赖性增加。然而，AMPA使通过NF200免疫反应性而非APP免疫反应性可视化的轴突损伤程度呈剂量依赖性增加。丙二酸和AMPA对白质完整性的其他评估的影响也不同，并且（14）C - 2 -脱氧葡萄糖放射自显影显示这两种毒素对脑代谢的初始影响不同。这些数据表明，在最初的兴奋性毒性或线粒体抑制后，常用的轴突损伤标记物量化白质损伤全部程度的能力不同。我们还证实在局灶性脑缺血大鼠模型中，这些标记物显示出不同程度的轴突损伤。因此，在旨在评估脑保护剂的临床前研究中，建议使用不止一种标记物来量化轴突损伤的真实程度。
