Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P < .05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P = .02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings.

中文翻译：

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全身和经皮褪黑激素给药可预防新生羔羊对围生期窒息的反应所致的神经病理学。

围产期窒息仍然是婴儿死亡和长期神经系统疾病的主要原因，尤其是在资源贫乏的国家。目前尚无神经保护性干预措施。褪黑激素（MLT）是一种有效的抗氧化剂，抗炎剂和抗凋亡剂，有望通过静脉（IV）或透皮疗法来保护大脑。我们旨在确定褪黑激素（静脉注射或透皮贴剂）对围产期窒息羔羊模型神经病理学的影响。新生羔羊出生时通过脐带闭塞引起窒息。从出生后30分钟开始将动物随机分配给褪黑激素（24小时内60 mg； IV或透皮贴剂）。在12和72小时进行了脑磁共振波谱（MRS）。动物（对照n ＝ 9；对照+ MLT n ＝ 6；窒息n ＝ 16；窒息+ MLT [IV n ＝ 14；对照n ＝ 14；对照n ＝ 14；对照n ＝ 6；对照n ＝ 16；对照n ＝ 14；对照n ＝ 14。补丁n = 4]）在72小时安乐死，收集脑脊液（CSF）和大脑进行分析。窒息导致严重的酸中毒（pH 6.9±0.0；乳酸9±2 mmol / L）并改变了脑病的决定因素。窒息羔羊的MRS乳酸：N-乙酰天门冬氨酸比在12小时时比对照组高2.5倍，在72小时时比对照组高3倍（P <.05）。褪黑素阻止了这种升高（与窒息相比降低了3.5倍； P = .02）。窒息显着增加脑白和灰质凋亡细胞死亡（激活的caspase-3），脂质过氧化（4HNE）和神经炎症（IBA-1）。这些变化被褪黑激素和静脉注射均显着缓解。全身或透皮新生儿褪黑激素的施用显着减少了与围生期窒息有关的神经病理学和脑病迹象。