Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA,
Dev Neurosci. 2020;42(2-4):124-134. doi: 10.1159/000511888. Epub 2020 Dec 10.
The striatal, primary sensorimotor cortical, and thalamic neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI that exhibits similar selective regional vulnerability, we tested the hypothesis that early treatment with sulforaphane, an activator of the Nrf2 transcription factor, protects vulnerable neurons from HI injury. Anesthetized piglets (aged 3-7 days) were subjected to 45 min of hypoxia and 7 min of airway occlusion. At 15 min after resuscitation, the piglets received intravenous vehicle or sulforaphane. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 31 ± 34% (±SD) that of sham-operated controls. Treatment with sulforaphane significantly increased viability to 77 ± 31%. In the sensorimotor cortex, neuronal viability was also increased; it was 59 ± 35% in the vehicle-treated and 89 ± 15% in the sulforaphane-treated animals. Treatment with sulforaphane increased the nuclear Nrf2 and γ-glu-tamylcysteine synthetase expression at 6 h of recovery in these regions. We conclude that systemic administration of sulforaphane 15 min after HI can induce the translocation of Nrf2 to the nucleus, increase expression of an enzyme involved in glutathione synthesis, and salvage neurons in the highly vulnerable putamen and sensorimotor cortex in a large-animal model of HI. Therefore, targeting Nrf2 activation soon after recovery from HI is a feasible approach for neuroprotection in the newborn brain.
纹状体、初级感觉运动皮层和丘脑神经元在足月新生儿中极易受到缺氧缺血（HI）的影响。在一种具有类似选择性区域易损性的 HI 仔猪模型中，我们检验了这样一种假设，即在 HI 后早期用 Nrf2 转录因子激活剂 sulforaphane 进行治疗，可以保护易损神经元免受 HI 损伤。麻醉仔猪（3-7 日龄）接受 45 分钟缺氧和 7 分钟气道阻塞。在复苏后 15 分钟，仔猪接受静脉注射载体或 sulforaphane。在 4 天的恢复期，载体处理的仔猪纹状体中存活神经元的密度为假手术对照的 31 ± 34%（±SD）。用 sulforaphane 治疗可使存活率显著增加至 77 ± 31%。在感觉运动皮层中，神经元的存活率也增加了；在载体处理的动物中为 59 ± 35%，在 sulforaphane 处理的动物中为 89 ± 15%。在这些区域，在 HI 后 6 小时恢复时，用 sulforaphane 治疗增加了核 Nrf2 和 γ-谷氨酰半胱氨酸合成酶的表达。我们的结论是，HI 后 15 分钟全身给予 sulforaphane 可以诱导 Nrf2 向核内易位，增加参与谷胱甘肽合成的酶的表达，并挽救在 HI 大动物模型中高度易损的纹状体和感觉运动皮层中的神经元。因此，在 HI 后恢复期间靶向 Nrf2 激活是新生儿大脑神经保护的一种可行方法。
