Adams Lauren E, Moss Hunter G, Lowe Danielle W, Brown Truman, Wiest Donald B, Hollis Bruce W, Singh Inderjit, Jenkins Dorothea D
Department of Pediatrics, 10 McLellan Banks Dr, Medical University of South Carolina, Charleston, SC 29425, USA.
Center for Biomedical Imaging, Department of Radiology, Medical University of South Carolina, 68 President St. Room 205, Charleston, SC 29425, USA.
Antioxidants (Basel). 2021 Mar 20;10(3):489. doi: 10.3390/antiox10030489.
Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O), followed by hypothermia alone or with -acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)D, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.
治疗性低温并不能改善合并围产期感染的新生儿缺氧缺血（HI）的预后，这是由于已充分描述的、预先存在的氧化应激和神经炎症缩短了治疗窗口。为了在损伤后实现有效的神经保护，我们必须首先确定并针对内毒素致敏性HI（LPS-HI）后立即发生的中枢神经系统代谢组学变化。我们假设LPS-HI会急性消耗还原型谷胱甘肽（GSH），这表明尽管对新生大鼠进行了低温治疗，但仍存在压倒性的氧化应激。出生后第7天的大鼠被随机分为假结扎组，或严重LPS-HI组（在右颈动脉结扎前4小时给予0.5mg/kg，90分钟8%氧气），随后单独进行低温治疗或联合使用N-乙酰半胱氨酸（25mg/kg）和维生素D（1,25(OH)D，0.05μg/kg）（NVD）。我们在LPS-HI之前、之后立即以及治疗后，通过连续7T磁共振波谱对体内中枢神经系统代谢物进行定量分析，并测定终末血浆药物浓度。与基线和假手术对照组相比，所有LPS-HI大鼠的GSH均显著降低。单独进行两小时的低温治疗并不能改善GSH水平，反而使谷氨酸+谷氨酰胺（GLX）增加。在给药后1小时内，NVD使GSH水平接近基线并抑制了GLX。NVD与低温联合应用可在LPS-HI后迅速改善细胞氧化还原状态，可能抑制重要的继发性损伤级联反应，并为低温神经保护争取更多时间。
