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

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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.