Motor Deficits Are Triggered by Reperfusion-Reoxygenation Injury as Diagnosed by MRI and by a Mechanism Involving Oxidants
Motor Deficits Are Triggered by Reperfusion-Reoxygenation Injury as Diagnosed by MRI and by a Mechanism Involving Oxidants
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DOI：
10.1523/jneurosci.5986-11.2012
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发表时间：
2012-04-18
影响因子：
5.3
通讯作者：
Tan, Sidhartha
中科院分区：
文献类型：
--
作者：
Drobyshevsky, Alexander;Luo, Kehuan;Tan, Sidhartha
脑瘫（CP）的早期病因尚不清楚，但怀疑是由于缺氧缺血（H-I）所致。在我们的兔CP模型中，MRI生物标志物，弥散加权成像上的表观扩散系数（ADC），预测了哪些胎儿会发生产后高渗症。存活的H-I胎儿经历再灌注再氧合，但在早期再灌注再氧合期间，一个亚群表现出持续下降的ADC，这可能代表更大的脑损伤（RepReOx）。我们假设再灌注-再氧化过程中的氧化应激是产后高渗的一个关键触发因素。我们研究了RepReOx是否能预测产后神经行为、指示氧化应激，以及RepReOx靶向抗氧化剂是否能改善运动缺陷，其中包括测试一种新的超氧化物歧化酶模拟物（MnTnHex-2-PyP）。79%妊娠兔（E25）子宫缺血40 min。在h - i期间、立即再灌注-再氧合期间以及h - i后4-72 h随访胎儿脑ADC。终点为E32时的产后神经学结局，H-I结束时的ADC， H-I和再灌注-再氧合期间ADC最低点，再灌注-再氧合前20分钟的ADC曲线下面积。在子宫缺血之前和/或之后给予RepReOx靶向抗氧化剂。RepReOx的新MRI-ADC生物标志物改善了对产后高渗症的预测。表现RepReOx的胎儿大脑比不表现RepReOx的胎儿大脑产生更多的超氧化物，线粒体损伤和少突胶质细胞丢失。抗氧化剂MnTnHex-2-PyP和抗坏血酸和Trolox联合使用可显著降低产后运动缺陷和RepReOx的程度。因此，早期损伤和后期运动缺陷之间的病因学联系可以通过MRI进行研究，并使我们能够区分导致运动缺陷的临界氧化应激和不会导致运动缺陷的非临界氧化应激。
The early antecedents of cerebral palsy (CP) are unknown but are suspected to be due to hypoxia-ischemia (H-I). In our rabbit model of CP, the MRI biomarker, apparent diffusion coefficient (ADC) on diffusion-weighted imaging, predicted which fetuses will develop postnatal hypertonia. Surviving H-I fetuses experience reperfusion-reoxygenation but a subpopulation manifested a continued decline of ADC during early reperfusion-reoxygenation, which possibly represented greater brain injury (RepReOx). We hypothesized that oxidative stress in reperfusion-reoxygenation is a critical trigger for postnatal hypertonia. We investigated whether RepReOx predicted postnatal neurobehavior, indicated oxidative stress, and whether targeting antioxidants at RepReOx ameliorated motor deficits, which included testing of a new superoxide dismutase mimic (MnTnHex-2-PyP). Rabbit dams, 79% gestation (E25), were subjected to 40 min uterine ischemia. Fetal brain ADC was followed during H-I, immediate reperfusion-reoxygenation, and 4-72 h after H-I. Endpoints were postnatal neurological outcome at E32, ADC at end of H-I, ADC nadir during H-I and reperfusion-reoxygenation, and area under ADC curve during the first 20 min of reperfusion-reoxygenation. Antioxidants targeting RepReOx were administered before and/or after uterine ischemia. The new MRI-ADC biomarker for RepReOx improved prediction of postnatal hypertonia. Greater superoxide production, mitochondrial injury, and oligodendroglial loss occurred in fetal brains exhibiting RepReOx than in those without. The antioxidants, MnTnHex-2-PyP and Ascorbate and Trolox combination, significantly decreased postnatal motor deficits and extent of RepReOx. The etiological link between early injury and later motor deficits can thus be investigated by MRI, and allows us to distinguish between critical oxidative stress that causes motor deficits and noncritical oxidative stress that does not.