Reducing the Burden of Neonatal Brain Injury:Assessment of Hypothermic & Melatonin Neuroprotection in an Inflammation-Sensitised Piglet Asphyxia Model

减轻新生儿脑损伤的负担：低温评估

• 批准号: MR/M006743/1
• 负责人: Nicola Robertson
• 金额: $ 126.6万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM006743%2F1
• 关键词: Reducing; Burden; Neonatal; Brain; Injury

Problems around the time of birth causing a lack of oxygen to the baby can cause disordered brain function called neonatal encephalopathy, which can result in long-term brain damage and cerebral palsy. Recent studies emphasise the critical importance of the body's response to harmful stimuli such as germs and damaged cells and how this response then amplifies the subsequent response to lack of oxygen. The germs may be present in the placenta or umbilical cord of the baby; the presence of these germs has been shown to augment the chance of developing severe neonatal encephalopathy and an abnormal outcome later in childhood. Although cooling babies with neonatal encephalopathy has been shown to be protective, there are some studies which now show that this protection may be less or absent when the body has mounted a response to germs. This may be because the cooling leads to cells that fight infection becoming dysfunctional or paralysed. There may be other medicines that are more protective in situations where there is already a response to germs in the body. One such medicine is melatonin, which is a natural hormone secreted by the pineal gland. In high doses we have already shown that melatonin protects the brain in situations where there is a lack of oxygen. Other studies have shown that melatonin protects the brain and body in situations where there is both a body response to germs and lack of oxygen. In the future in order to administer the correct medicine to babies with neonatal encephalopathy it will be important to try to find out whether a baby has neonatal encephalopathy from just a lack of oxygen or whether there is a combination of lack of oxygen and a response to germs in the body, placenta or umbilical cord. We need to try to find markers in the blood that can give us this idea in the first few hours after the baby is born. We have studied a piglet model of a pure lack of oxygen for almost 20 years at UCL. We now wish to adapt this model to reflect the type of neonatal encephalopathy that presents in the labour ward across the world. To do this we need to adapt the piglet model. We plan to perform three related studies:Study 1: We wish to establish this new model. To replicate the the body's response to germs we will inject a substance called lipopolysaccharide (LPS) which is a molecule found in the outer membrane of gram-negative bacteria and which elicits a strong immune response. We will start the infusion of LPS 4 hours before the period of the lack of oxygen (2micrograms/kg bolus and 1 micrograms/kg/h infusion over the entire experiment). As we know that LPS will augment the body's response to a lack of oxygen we will need to reduce the duration of the oxygen lack to ensure we are comparing similar levels of injury (pure lack of oxygen versus LPS with lack of oxygen). Study 2: We will compare the relative protective response to cooling and melatonin. We will measure the immune responsiveness and see if this is related to the brain protection in both models. Study 3: we will explore tests that will give us more information on the nature and extent of brain injury in babies with neonatal encephalopathy. At present there is no bedside test that can be used to reliably predict outcome and whether there is pure lack of oxygen or a mixture of germs and the body's response and lack of oxygen. A simple blood test would be an attractive option. Recently chemicals in the blood, including genetic fragments called microRNAs, have been found in the blood stream following brain damage and may indicate the extent of the damage. We therefore plan to use state-of-the-art technology in our piglet model to develop a panel of chemicals that can be measured together in a single blood test to predict the extent of brain damage.These studies will allow the future tailoring of neuroprotective treatments to specific babies and the improvement of outcome in neonatal encephalopathy across the world.

出生时的问题导致婴儿缺氧会导致称为新生儿脑病的脑功能紊乱，这可能导致长期脑损伤和脑瘫。最近的研究强调了身体对有害刺激（如细菌和受损细胞）的反应的至关重要性，以及这种反应如何放大随后对缺氧的反应。这些细菌可能存在于婴儿的胎盘或脐带中;这些细菌的存在已被证明会增加发生严重新生儿脑病的机会，并在儿童后期出现异常结果。虽然冷却患有新生儿脑病的婴儿已被证明是保护性的，但现在有一些研究表明，当身体对细菌产生反应时，这种保护可能会减少或消失。这可能是因为冷却导致对抗感染的细胞功能失调或瘫痪。可能有其他药物在体内已经对细菌有反应的情况下更具保护性。其中一种药物是褪黑激素，这是一种由松果体分泌的天然激素。在高剂量的情况下，我们已经证明褪黑激素在缺氧的情况下可以保护大脑。其他研究表明，褪黑激素在身体对细菌和缺氧都有反应的情况下保护大脑和身体。在未来，为了给患有新生儿脑病的婴儿服用正确的药物，重要的是要找出婴儿是否患有新生儿脑病，仅仅是因为缺氧，或者是否是缺氧和对身体，胎盘或脐带中细菌的反应的组合。我们需要在婴儿出生后的最初几个小时内找到血液中的标记物。我们在UCL研究了近20年的纯缺氧仔猪模型。我们现在希望调整该模型以反映世界各地产房中出现的新生儿脑病类型。要做到这一点，我们需要调整小猪模型。我们计划进行三个相关的研究：研究1：我们希望建立这个新模型。为了复制身体对细菌的反应，我们将注射一种称为脂多糖（LPS）的物质，这是一种在革兰氏阴性细菌外膜中发现的分子，它能激发强烈的免疫反应。我们将在缺氧期前4小时开始输注LPS（在整个实验中2微克/kg推注和1微克/kg/h输注）。正如我们所知，LPS会增强身体对缺氧的反应，我们需要减少缺氧的持续时间，以确保我们比较相似的损伤水平（纯缺氧与LPS缺氧）。研究2：我们将比较冷却和褪黑激素的相对保护反应。我们将测量免疫反应性，看看这是否与两种模型中的大脑保护有关。研究3：我们将探索能为我们提供更多关于新生儿脑病婴儿脑损伤的性质和程度的信息的测试。目前还没有床旁测试可以用来可靠地预测结果，以及是否有纯粹的缺氧或细菌和身体的反应和缺氧的混合物。一个简单的血液测试将是一个有吸引力的选择。最近，血液中的化学物质，包括称为microRNA的遗传片段，在脑损伤后的血流中被发现，并可能表明损伤的程度。因此，我们计划在我们的小猪模型中使用最先进的技术，开发一组化学物质，这些化学物质可以在一次血液测试中一起测量，以预测脑损伤的程度。这些研究将允许未来为特定婴儿定制神经保护治疗，并改善世界各地新生儿脑病的结果。

项目成果

Using animal models to improve care of neonatal encephalopathy.

使用动物模型改善新生儿脑病的护理。

• DOI: 10.1136/archdischild-2015-309927
• 发表时间: 2016
• 期刊: Archives of disease in childhood. Education and practice edition
• 作者: Lingam I

Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia-ischemia.

• DOI: 10.1038/s41390-021-01584-6
• 发表时间: 2022-05
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Martinello KA;Meehan C;Avdic-Belltheus A;Lingam I;Mutshiya T;Yang Q;Akin MA;Price D;Sokolska M;Bainbridge A;Hristova M;Tachtsidis I;Tann CJ;Peebles D;Hagberg H;Wolfs TGAM;Klein N;Kramer BW;Fleiss B;Gressens P;Golay X;Robertson NJ
• 通讯作者: Robertson NJ

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes.

• DOI: 10.1038/s41390-021-01438-1
• 发表时间: 2022-07
• 期刊: PEDIATRIC RESEARCH
• 影响因子: 3.6
• 作者: Pang, Raymand;Mujuni, Brian M.;Martinello, Kathryn A.;Webb, Emily L.;Nalwoga, Angela;Ssekyewa, Julius;Musoke, Margaret;Kurinczuk, Jennifer J.;Sewegaba, Margaret;Cowan, Frances M.;Cose, Stephen;Nakakeeto, Margaret;Elliott, Alison M.;Sebire, Neil J.;Klein, Nigel;Robertson, Nicola J.;Tann, Cally J.
• 通讯作者: Tann, Cally J.

Management and investigation of neonatal encephalopathy: 2017 update.

• DOI: 10.1136/archdischild-2015-309639
• 发表时间: 2017-07
• 期刊: Archives of disease in childhood. Fetal and neonatal edition
• 作者: Martinello K;Hart AR;Yap S;Mitra S;Robertson NJ
• 通讯作者: Robertson NJ

Isoflurane Exposure Induces Cell Death, Microglial Activation and Modifies the Expression of Genes Supporting Neurodevelopment and Cognitive Function in the Male Newborn Piglet Brain.

• DOI: 10.1371/journal.pone.0166784
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Broad KD;Hassell J;Fleiss B;Kawano G;Ezzati M;Rocha-Ferreira E;Hristova M;Bennett K;Fierens I;Burnett R;Chaban B;Alonso-Alconada D;Oliver-Taylor A;Tachsidis I;Rostami J;Gressens P;Sanders RD;Robertson NJ
• 通讯作者: Robertson NJ