Data_Sheet_1_Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic–ischemic encephalopathy.docx

Hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good (n = 10), or poor outcomes (n = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE.

缺氧缺血性脑病（Hypoxic–ischemic encephalopathy, HIE）是新生儿发病与死亡的主要诱因。尽管治疗性低温是其有效的临床治疗手段，但仍常有严重的慢性神经功能缺损残留。长链ω-3多不饱和脂肪酸（polyunsaturated fatty acids, PUFAs）——二十二碳六烯酸（docosahexaenoic, DHA）与二十碳五烯酸（eicosapentaenoic, EPA）——在疾病急性期后阶段展现出治疗潜力。为明确HIE与治疗性低温对PUFAs的影响，本研究首次量化分析了HIE及治疗性低温对血液PUFA水平与脂质过氧化的作用。本研究采用横断面研究设计，将接受治疗性低温的中重度HIE新生儿（以下简称sHIE组）的血液样本，与未接受治疗性低温的轻度HIE新生儿及健康对照的血液样本进行对比。sHIE组进一步根据颅脑MRI预测的预后分为良好预后亚组（n=10）与不良预后亚组（n=10，其中9例继发脑瘫）。研究对细胞沉淀进行脂肪酸含量分析，并对血浆样本检测脂质过氧化产物、硫代巴比妥酸反应物质以及4-羟基-2-壬烯醛。ω-3指数（即DHA+EPA所占百分比）在对照组与HIE组间无显著差异；但在sHIE组中，不良预后亚组的ω-3指数显著低于良好预后亚组。与轻度HIE组及对照组相比，sHIE组的估算Δ-6去饱和酶活性显著降低；而良好预后的sHIE亚组中，亚油酸水平显著升高。长链ω-3 PUFAs水平降低与HIE及治疗性低温后的不良预后相关，其潜在机制可能为生物合成减少与组织摄取降低。本研究推测，除现有治疗手段外，长链ω-3 PUFA干预或可改善sHIE患儿的神经预后。