Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287-4961, USA.
Dev Neurosci. 2011;33(3-4):299-311. doi: 10.1159/000327243. Epub 2011 Jun 24.
Striatal neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI, striatal neurons develop oxidative stress and organelle disruption by 3-6 h of recovery and ischemic cytopathology over 6-24 h of recovery. We tested the hypothesis that early treatment with the antioxidants EUK-134 (a manganese-salen derivative that acts as a scavenger of superoxide, hydrogen peroxide, nitric oxide or NO and peroxynitrite) or edaravone (MCI-186, a scavenger of hydroxyl radical and NO) protects striatal neurons from HI. Anesthetized newborn piglets were subjected to 40 min of hypoxia and 7 min of airway occlusion. At 30 min after resuscitation, the piglets received vehicle, EUK-134 or edaravone. Drug treatment did not affect arterial blood pressure, blood gases, blood glucose or rectal temperature. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 12 ± 6% (±SD) of sham-operated control density. Treatment with EUK-134 increased viability to 41 ± 17%, and treatment with edaravone increased viability to 39 ± 19%. In the caudate nucleus, neuronal viability was increased from 54 ± 11% in the vehicle group to 78 ± 15% in the EUK-134 group and to 73 ± 13% in the edaravone group. Antioxidant drug treatment accelerated recovery from neurologic deficits and decreased oxidative and nitrative damage to nucleic acids. Treatment with EUK-134 reduced the HI-induced formation of protein carbonyl groups and tyrosine nitration at 3 h of recovery. We conclude that systemic administration of antioxidant agents by 30 min after resuscitation from HI can reduce oxidative stress and salvage neurons in the highly vulnerable striatum in a large-animal model of neonatal HI. Therefore, oxidative stress is an important mechanism for this injury, and antioxidant therapy is a rational, mechanism-based approach to neuroprotection in the newborn brain.
纹状体神经元在足月新生儿缺氧缺血（HI）中非常脆弱。在 HI 的仔猪模型中，纹状体神经元在恢复 3-6 小时后会产生氧化应激和细胞器破坏，在恢复 6-24 小时后会出现缺血性细胞病理学。我们检验了以下假设，即在 HI 复苏后 30 分钟内用抗氧化剂 EUK-134（一种锰-西罗莫司衍生物，可作为超氧化物、过氧化氢、一氧化氮或 NO 和过氧亚硝酸盐的清除剂）或依达拉奉（MCI-186，羟自由基和 NO 的清除剂）进行早期治疗，可以保护纹状体神经元免受 HI 损伤。麻醉后的新生仔猪经历 40 分钟的缺氧和 7 分钟的气道阻塞。在复苏后 30 分钟，仔猪接受载体、EUK-134 或依达拉奉治疗。药物治疗未影响动脉血压、血气、血糖或直肠温度。在恢复的第 4 天，载体处理的仔猪壳核中的存活神经元密度为假手术对照密度的 12±6%（±SD）。EUK-134 治疗可将存活率提高至 41±17%，依达拉奉治疗可将存活率提高至 39±19%。在尾状核中，神经元存活率从载体组的 54±11%增加到 EUK-134 组的 78±15%和依达拉奉组的 73±13%。抗氧化药物治疗加速了神经功能缺损的恢复，并减少了核酸的氧化和硝化损伤。EUK-134 治疗可减少 HI 后 3 小时恢复时诱导的蛋白质羰基形成和酪氨酸硝化。我们得出结论，在 HI 复苏后 30 分钟内全身给予抗氧化剂可以减少氧化应激并挽救大型动物新生 HI 模型中高度脆弱的纹状体中的神经元。因此，氧化应激是这种损伤的重要机制，抗氧化治疗是一种合理的、基于机制的新生儿脑神经保护方法。
