FETAL BRAIN INJURY RESULTING FROM INTRAUTERINE INFECTION: LONG TERM CONSEQUENCES AND THE POTENTIAL FOR INTERVENTION
Funder
National Health and Medical Research Council
Funding Amount
$452,640.00
Summary
Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. Unfortunately, at present, it is not possible to prevent or effectively treat brain damage in the fetu ....Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. Unfortunately, at present, it is not possible to prevent or effectively treat brain damage in the fetus or newborn, partly due to ignorance about how and when the damage is occurring. In recent years it has become evident that infections in the mother, may be linked to both premature birth and brain damage. It has been proposed that the certain chemicals (cytokines) which are released during an infection can across the placenta to the fetus, causing inflammatory changes that lead to brain damage. However, although associations have been shown in studies of women, there is little evidence that infections actually cause brain damage in the fetus. This project will define the effects of an inflammation inducing chemical (bacterial endotoxin) on the fetal brain and the pattern of inflammation it sets up in the fetus. We will also examine the effects of brain damage caused by endotoxin in the newborn lamb, and relate this to alterations in behaviour. Once we have defined the effects of endotoxin on brain structure, we will test the effects of chemicals that are known to block the actions of inflammatory cytokines. We hope that by blocking the chemical pathway that leads to the production of harmful cytokines we may be able to prevent brain injury from occurring when the fetus is exposed to an infection in the mother. It is expected that this project will provide important information that helps us to understand how infection in the mother can cause brain injury in the fetus. This information is vital if strategies to prevent or treat brain injury are to be developed.Read moreRead less
Creatine Synthesis And Transport In The Fetus - Critical Regulation Of Energy Supply For Fetal Growth & Survival?
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Survival at birth depends on the baby being able to breathe effectively, to maintain adequate blood flow to every organ, and for the brain to coordinate these activities. Failure of any one of these will result in death. In this application we propose that the ability of the fetus and newborn baby to obtain adequate supplies of CREATINE is essential for survival, because this substance is essential for maintaining energy turnover in all cells in the body. In the adult, CREATINE is obtained eithe ....Survival at birth depends on the baby being able to breathe effectively, to maintain adequate blood flow to every organ, and for the brain to coordinate these activities. Failure of any one of these will result in death. In this application we propose that the ability of the fetus and newborn baby to obtain adequate supplies of CREATINE is essential for survival, because this substance is essential for maintaining energy turnover in all cells in the body. In the adult, CREATINE is obtained either from the diet (after absorption from the gut), or after synthesis in, and release from the liver. We do not know how fetal tissues obtain CREATINE, but we do know that when CREATINE is too low the fetus is likely to die, and that if extra CREATINE is supplied in the mother's diet the fetus is more likely to survive profound asphyxia at birth. In this project, in pregnant animals we will determine if fetal tissues can synthesize and take up CREATINE, and if providing extra CREATINE in the maternal diet throughout pregnancy can protect the heart, brain and breathing apparatus from the damaging effects of asphyxia or low oxygen (hypoxia). If successful, we will have developed a new treatment for pregnant women that protects their unborn baby from the dangers of birth asphyxia.Read moreRead less
Neurosteroid Mediated Protection After Birth: Approaches For Maximising Protective Steroid Levels In The Neonatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$450,703.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the ....Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.Read moreRead less
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less
Contribution Of Disturbed Blood Flow And Cerebral Metabolism To White Matter Damage In The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$369,375.00
Summary
It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral ....It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral palsy. Such outcomes are often associated with the presence of asphyxia and infection during pregnancy, leading to the belief that the damage first arises while the baby is still in utero. In this application we suggest that asphyxia and-or infection during pregnancy cause prolonged disturbances in the regulation of blood flow and integrity of the blood-brain barrier in the developing brain, together with changes in metabolism that result in accumulation of prostaglandins and the toxic hydroxyl radical, leading irreversibly to cell death. If this series of events proves to be true, we have suggested and will test several protocols for protecting the fetal brain, which should be readily translatable to clinical practice.Read moreRead less
Neuroactive Steroids In The Developing Brain: Potential For Preventing Perinatal Brain Damage
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown tha ....Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown that protective neuroactive steroids are present in very large amounts in the fetal brain. Steroids produced by the placenta are converted to these neuroactive products by enzymes in the brain leading to the high levels that are seen during fetal life. Certain adverse conditions during pregnancy as well as preterm birth may cause marked changes in the balance of steroids that could increase susceptibility to brain injury. We have found that areas of the brain, where damage most often occurs, normally contain the highest amount of protective steroids, but only in late pregnancy. This suggests that disturbances that lower steroid production in these areas could contribute to the death of cells, particularly in mid-pregnancy and after premature birth. In the proposed studies, we will examine whether a toxic balance of steroids develops following adverse events in pregnancy as well as the areas of the brain where this is most pronounced. We will examine the changes in the expression of enzymes that can potentially cause the accumulation of protective steroids in the brain. We will then examine treatments that can raise the concentration of steroids and determine which combination of steroids best reduces cell death and brain injury following complications during pregnancy. The findings of this work will indicate the best therapeutic approach that may be adopted to modify the concentration of certain steroids so as to reduce the risk of brain damage in the fetus and neonate.Read moreRead less
PROTECTING THE PRETERM FETAL BRAIN FROM HYPOXIA AND INFECTION: A HEALTHY START TO LIFE.
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. In recent years it has become evident that infections in the mother may be linked to both premature bi ....Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. In recent years it has become evident that infections in the mother may be linked to both premature birth and brain damage. It has been proposed that certain chemicals (cytokines), which are released during an infection, can cross the placenta to the fetus causing inflammatory changes that lead to brain damage. We have shown that an inflammatory inducing chemical (bacterial endotoxin) administered to immature fetal sheep induces brain damage similar to that seen in cerebral palsy. This provides an excellent model for testing agents that are known to block the action of cytokines and other markers of inflammation; currently there is no effective strategy for the treatment or prevention of hypoxia and inflammatory induced injury of the brain partly due to our ignorance about how and when the damage is occurring. We will test the effects of two chemicals; N-acetyl cysteine, which is known to block the generation of inflammatory cytokines, and the naturally occurring glycoprotein erythropoietin, which prevents death of neurons (apoptosis). We hope that by blocking these pathways we may be able to prevent brain injury from occurring when the immature fetus is exposed to an infection during gestation. We expect that this project will provide important novel information that helps us to understand how infection in the mother can cause brain injury in the fetus and provide a new approach for strategies to prevent or treat brain injury.Read moreRead less
Cerebrovascular Effects Of Intrauterine Hypoxia: Contribution To Perinatal Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
During pregnancy, delivery of oxygen and nutrients to the growing fetus is sometimes disturbed, and can lead to injury of the developing brain. In this project we investigate the idea that low oxygen (hypoxia) causes brain demage to blood vessels in the fetal brain, and new blood vessesl produced in an attempt to repair this damage are fragile and prone to rupture, explaining the high incidence of bleeding in the brain of prematurely-born and full term infants that experience birth hypoxia.
Role Of Kynurenine Metabolites In Causing And Preventing Excitotoxic Brain Damage In The Fetus.
Funder
National Health and Medical Research Council
Funding Amount
$92,815.00
Summary
Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic ....Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic substance - QUINOLINIC ACID - in the fetal brain and circulation. The increased production of QUINOLINIC ACID occurs because certain cells react to the low oxygen and infectious conditions - these cells include MICROGLIA, a cell type in the brain. Little is currently known about MICROGLIA in the developing brain. We will therefore study the effects of hypoxia and infection in fetal sheep, and we will determine how these conditions affect MICROGLIA and the synthesis of QUINOLINIC ACID in the fetal brain. The capacity of the brain to produce QUINOLINIC ACID is closely related to the dietary intake of the essential amino acid TRYPTOPHAN, and it is decreased when synthetic analogues of tryptophan are infused. Therefore, we have devised a treatment regime using these tryptophan analogues to prevent increases of QUINOLINIC ACID concnetrations in the fetal brain, and we propose that a simple treament is at hand to reduce the incidence of perinatal brain damage in human pregnancies.Read moreRead less
Compromised Fetal Brain Development: Neurogenesis And The Potential For Therapeutic Intervention.
Funder
National Health and Medical Research Council
Funding Amount
$497,280.00
Summary
Lack of oxygen to the fetal brain during pregnancy is thought to be the main causes of brain injury in newborns. Some of these infants will suffer developmental and behavioural problems including cerebral palsy, schizophrenia and epilepsy. Currently, there is no effective treatment to redress these changes in brain development and this is one of the major challenges in perinatal medicine today. We have previously shown in a guinea pig model of chronic placental insufficiency (reduced oxygen and ....Lack of oxygen to the fetal brain during pregnancy is thought to be the main causes of brain injury in newborns. Some of these infants will suffer developmental and behavioural problems including cerebral palsy, schizophrenia and epilepsy. Currently, there is no effective treatment to redress these changes in brain development and this is one of the major challenges in perinatal medicine today. We have previously shown in a guinea pig model of chronic placental insufficiency (reduced oxygen and nutrient levels during pregnancy) that there is a reduction in neurons and in the connections between them. This may result from a reduction in number of newly generated neurons (neurogenesis), or an increase in neuronal death (apoptosis), or both. To develop therapeutic strategies to improve brain growth and ultimately functional recovery, we must understand the mechanisms which lead to these brain changes. In this project, we will use our guinea pig model to: 1) determine whether a suboptimal fetal environment decreases neuronal numbers by influencing neurogenesis, apoptosis or both, 2) study changes in the compromised brain environment which are likely to influence apoptosis and neurogenesis, 3) determine whether a suboptimal fetal environment has long-term effects on adult neurogenesis and 4) determine whether treatment with erythropoietin (Epo), a naturally occurring hormone, can resolve deficits in brain development and function. Epo is an exciting candidate as it is, or is in the process of being used to treat stroke and newborn asphyxiation. Epo has also been shown to prevent neuronal death and promote neurogenesis following brain injury. Understanding the mechanisms and finding effective treatments for brain damage is a vital area of endeavour if we are to help infants develop their maximum potential and reduce the enormous social, economic and educational burden which must be borne by the individual and society in general when things go wrong during pregnancy.Read moreRead less