MICA: Optimising brain protection and reducing birth asphyxia disability: safety and efficacy of early high dose MELATONIN and COOLING with late EPO

MICA：优化大脑保护并减少出生窒息残疾：早期高剂量褪黑素和晚期 EPO 冷却的安全性和有效性

• 批准号: MR/P025978/1
• 负责人: Nicola Robertson
• 金额: $ 129.88万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP025978%2F1
• 关键词: MICA; Optimising; brain; protection; reducing

Problems around the time of birth causing a lack of oxygen to the baby can cause disordered brain function called neonatal encephalopathy (NE), which can result in long term brain damage and cerebral palsy. Cooling a baby by 3 degrees Celsius for three days as soon as possible after birth has been shown to be safe and leads to long term brain protection and improved outcome even to school age. The number of babies that need to be treated with cooling to prevent one from being dead or disabled is 6-7. Cooling has been endorsed by the National Institute for Clinical Excellence (NICE) and adopted in neonatal intensive care units around the UK for babies with moderate to severe NE. However, although cooling is a major step forward for babies with NE, 44-53% of babies still have adverse outcomes. Over the last 5 years, studies have been performed in the laboratory of N Robertson (PI) and S Juul (co-applicant) on 1. melatonin and 2. erythropoietin (Epo) respectively; these studies have both shown that adding one of these agents to cooling is safe and leads to better outcomes in animals (melatonin) and in animals and babies (Epo). These agents act at different parts of the cascade of injury after hypoxia: 1. Melatonin is a naturally occurring hormone produced by the pineal gland which entrains the day/night cycle at physiological levels. At higher levels (plasma levels 10,000 times higher than normal night time levels), melatonin has powerful non-receptor actions to scavenge damaging free radicals. Our studies have shown the critical importance of reaching the therapeutic range of melatonin as quickly as possible after the injury for most benefit. Our collaboration with the pharmaceutical company, Chiesi, started in 2013 following our initial study showing significant augmentation of brain protection with melatonin at 10 mins after hypoxia. Chiesi has developed a novel melatonin formulation which is safe for babies; this new formulation was assessed recently in our laboratory and the optimal rate and dosing of melatonin to achieve therapeutic levels at 3h rather than 8h has been calculated. 2. Epo is a protein originally identified for its role in stimulating red blood cell generation. Epo has brain protection and repair and regeneration properties and have been shown to be protective when starting in the subacute phase up to 1 week after the injury in animals and at 16.5 h in babies with cooling.S Juul has been a leader in the Epo brain protection field and has unique knowledge of dose response and safety and is PI on the 2 clinical trials of Epo brain protection in the USA. Our aim is to perform a study which addresses the following questions:1. Does the combination of an optimised high dose melatonin given early on at 1h after the injury and at a faster infusion rate and late Epo at 24h after rewarming lead to better brain protection than cooling alone (triple versus single therapy)2. Does triple therapy (Cooling, melatonin and Epo) lead to bettie protection than double therapy (Cooling play melatonin or cooling plus Epo)3. Does the optimised high dose melatonin with therapeutic levels achieved in 3h after injury lead to improved protection compared to our previous protocol where therapeutic levels were achieved at 8h after injury. We will use an established piglet intensive care model of NE to address these questions. Intensive care and monitoring can be given to the piglet, the size allows for the same intravenous lines and catheters to be used as in babies, the medications are all based on protocols from the NICU and the maturational stage of the piglet brain is similar to human brain with the brain growth spurt occurring around birth. We use the same 3 Tesla MRI system and same sequences as we do in babies with NE, making the data clinically relevant and translational. These data, if positive, will be translated to clinical trials in babies and could lead to significant benefit to outcomes.

出生时的问题导致婴儿缺氧会导致称为新生儿脑病（NE）的脑功能紊乱，这可能导致长期脑损伤和脑瘫。在出生后尽快将婴儿冷却3摄氏度三天已被证明是安全的，并导致长期的大脑保护和改善的结果，甚至到学龄。需要冷却以防止死亡或残疾的婴儿人数为6-7人。冷却已经得到了国家临床优化研究所（NICE）的认可，并在英国各地的新生儿重症监护病房被采用，用于治疗中度至重度NE的婴儿。然而，尽管冷却是NE婴儿的一个重要进步，但44-53%的婴儿仍然有不良后果。在过去5年中，在N Robertson（PI）和S Juul（共同申请人）的实验室中对1.褪黑激素和2.促红细胞生成素（Epo）;这些研究都表明，添加这些药物之一的冷却是安全的，并导致更好的结果在动物（褪黑激素）和动物和婴儿（Epo）。这些药物作用于缺氧后损伤级联反应的不同部位：1.褪黑激素是一种自然产生的激素，由松果体产生，在生理水平上参与昼夜循环。在更高的水平（血浆水平比正常的夜间水平高10，000倍），褪黑激素具有强大的非受体作用，以消除有害的自由基。我们的研究表明，在损伤后尽快达到褪黑激素的治疗范围以获得最大益处至关重要。我们与制药公司Chiesi的合作始于2013年，此前我们的初步研究显示，褪黑激素在缺氧后10分钟显著增强了大脑保护作用。Chiesi开发了一种对婴儿安全的新型褪黑激素制剂;我们的实验室最近对这种新制剂进行了评估，并计算了褪黑激素在3小时而不是8小时达到治疗水平的最佳速率和剂量。2.促红细胞生成素是一种蛋白质，最初被鉴定为刺激红细胞生成的蛋白质。Epo具有脑保护、修复和再生的特性，已被证明在动物损伤后1周内的亚急性期和婴儿冷却后16.5小时内具有保护作用。S Juul一直是Epo脑保护领域的领导者，对剂量反应和安全性具有独特的知识，是美国2项Epo脑保护临床试验的PI。我们的目的是进行一项研究，解决以下问题：1。在损伤后1小时早期以更快的输注速率给予优化的高剂量褪黑激素和在复温后24小时给予晚期Epo的组合是否比单独冷却更好地保护大脑（三联疗法与单一疗法）2。三联疗法（冷却，褪黑激素和促红细胞生成素）是否比双重疗法（冷却，褪黑激素或冷却加促红细胞生成素）更有效？与我们之前的方案相比，优化的高剂量褪黑激素在损伤后3小时内达到治疗水平是否会导致保护作用的改善，其中在损伤后8小时达到治疗水平。我们将使用一个既定的仔猪重症监护模型的NE来解决这些问题。可以对仔猪进行重症监护和监测，尺寸允许使用与婴儿相同的静脉注射管线和导管，药物治疗都基于NICU的协议，仔猪大脑的成熟阶段与人类大脑相似，大脑生长突增发生在出生前后。我们使用与NE婴儿相同的3特斯拉MRI系统和相同的序列，使数据具有临床相关性和转化性。这些数据如果是积极的，将被转化为婴儿的临床试验，并可能导致显着的好处的结果。

项目成果

Melatonin for Neonatal Encephalopathy: From Bench to Bedside.

• DOI: 10.3390/ijms22115481
• 发表时间: 2021-05-22
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Pang R;Advic-Belltheus A;Meehan C;Fullen DJ;Golay X;Robertson NJ
• 通讯作者: Robertson NJ

Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia.

• DOI: 10.1093/braincomms/fcaa211
• 发表时间: 2021
• 期刊: Brain communications
• 影响因子: 4.8
• 作者: Pang R;Avdic-Belltheus A;Meehan C;Martinello K;Mutshiya T;Yang Q;Sokolska M;Torrealdea F;Hristova M;Bainbridge A;Golay X;Juul SE;Robertson NJ
• 通讯作者: Robertson NJ

Proton Magnetic Resonance Spectroscopy Lactate/N-Acetylaspartate Within 48 h Predicts Cell Death Following Varied Neuroprotective Interventions in a Piglet Model of Hypoxia-Ischemia With and Without Inflammation-Sensitization.

• DOI: 10.3389/fneur.2020.00883
• 发表时间: 2020
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Pang R;Martinello KA;Meehan C;Avdic-Belltheus A;Lingam I;Sokolska M;Mutshiya T;Bainbridge A;Golay X;Robertson NJ
• 通讯作者: Robertson NJ