Tuor Ursula I, Zhao Zonghang, Barber Philip A, Qiao Min
Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, T2N 4N1, Canada.
BMC Neurosci. 2016 May 26;17(1):28. doi: 10.1186/s12868-016-0263-x.
In the current study, a transient cerebral ischemia producing selective cell death was designated a mild ischemic insult. A comparable insult in humans is a transient ischemic attack (TIA) that is associated with functional recovery but can have imaging evidence of minor ischemic damage including cerebral atrophy. A TIA also predicts a high risk for early recurrence of a stroke or TIA and thus multiple ischemic insults are not uncommon. Not well understood is what the effect of differing recovery times between mild ischemic insults has on their pathophysiology. We investigated whether cumulative brain damage would differ if recurrence of a mild ischemic insult occurred at 1 or 3 days after a first insult.
A transient episode of middle cerebral artery occlusion via microclip was produced to elicit mild ischemic changes-predominantly scattered necrosis. This was followed 1 or 3 days later by a repeat of the same insult. Brain damage assessed histologically 7 days later was substantially greater in the 1 day recurrent group than the 3 days recurrent group, with areas of damage consisting predominantly of regions of incomplete infarction and pannecrosis in the 1 day group but predominantly regions of selective necrosis and smaller areas of incomplete infarction in the 3 days group (P < 0.05). Enhanced injury was reflected by greater number of cells staining for macrophages/microglia with ED1 and greater alterations in GFAP staining of reactive astrocytes in the 1 day than 3 days recurrent groups. The differential susceptibility to injury did not correspond to higher levels of injurious factors present at the time of the second insult such as BBB disruption or increased cytokines (tumor necrosis factor). Microglial activation, with potential for some beneficial effects, appeared greater at 3 days than 1 day. Also blood analysis demonstrated changes that included an acute increase in granulocytes and decrease in platelets at 1 day compared to 3 days post transient ischemia.
Dynamic changes in multiple inflammatory responses likely contribute to the time dependence of the extent of damage produced by recurrent mild ischemic insults. The time of mild stroke recurrence is crucial with early recurrence producing greater damage than subacute recurrence and this supports urgency for determining and implementing optimal stroke management directly after a TIA.
在本研究中，导致选择性细胞死亡的短暂性脑缺血被定义为轻度缺血性损伤。在人类中，类似的损伤是短暂性脑缺血发作（TIA），它与功能恢复相关，但可能有轻微缺血性损伤的影像学证据，包括脑萎缩。TIA还预示着中风或TIA早期复发的高风险，因此多次缺血性损伤并不罕见。轻度缺血性损伤之间不同恢复时间对其病理生理学有何影响尚不清楚。我们研究了如果轻度缺血性损伤在首次损伤后1天或3天复发，累积脑损伤是否会有所不同。
通过微血管夹造成短暂性大脑中动脉闭塞，引发轻度缺血性改变——主要是散在性坏死。1天或3天后重复相同损伤。7天后组织学评估显示，1天复发组的脑损伤明显大于3天复发组，1天组的损伤区域主要由不完全梗死和全坏死区域组成，而3天组主要是选择性坏死区域和较小的不完全梗死区域（P<0.05）。与3天复发组相比，1天复发组中巨噬细胞/小胶质细胞ED1染色的细胞数量更多，反应性星形胶质细胞GFAP染色的改变更大，这反映了损伤增强。对损伤的不同易感性与第二次损伤时存在的更高水平的损伤因子（如血脑屏障破坏或细胞因子增加（肿瘤坏死因子））不相符。小胶质细胞激活可能有一些有益作用，3天时似乎比1天时更明显。此外，血液分析显示，与短暂性缺血后3天相比，1天时粒细胞急性增加，血小板减少。
多种炎症反应的动态变化可能导致复发性轻度缺血性损伤所产生损伤程度的时间依赖性。轻度中风复发时间至关重要早复发比亚急性复发造成的损伤更大，这支持了在TIA后立即确定并实施最佳中风管理的紧迫性。
