New And Improved Treatment Strategies For Neonatal Seizures
Funder
National Health and Medical Research Council
Funding Amount
$883,209.00
Summary
Around 10% of neonates in Australia are diagnosed with seizures each year. Seizures worsen neurodevelopmental outcome following hypoxic brain injury. Despite evidence of the limited effectiveness and potential neurotoxicity of current anti-seizure medication, treatment has not changed for many decades. The objective of this study is to optimise treatment of neonatal seizures with a compound that is effective and does not cause harm, or indeed provides neuroprotection for the compromised brain.
Flavonoids are widely consumed in the diet in food, beverages and herbal preparations. They have diverse actions on the body. We wish to investigate how they might affect brain function. One of the most important transmitters in the brain is a chemical known as GABA. Many known CNS drugs, such as alcohol and the benzodiazepine Valium, influence the action of GABA as a transmitter. These drugs enhance the action of GABA in activating particular receptors in the brain. We have discovered that apig ....Flavonoids are widely consumed in the diet in food, beverages and herbal preparations. They have diverse actions on the body. We wish to investigate how they might affect brain function. One of the most important transmitters in the brain is a chemical known as GABA. Many known CNS drugs, such as alcohol and the benzodiazepine Valium, influence the action of GABA as a transmitter. These drugs enhance the action of GABA in activating particular receptors in the brain. We have discovered that apigenin, a flavonoid found in many herbal preparations and in beverages such as camomile tea, has a special action on GABA in that it enhances the enhancing action of benzodiazepines on GABA receptors. This is a novel mode of drug action that needs to be explored further. We will study the actions of a range of flavonoids known to occur in various popular products such as soy milk, red wine and green tea for their effects on GABA receptors. From the results we plan to design and synthesise new substances with a view to discovering new therapeutic agents to treat a range of CNS disorders, such as anxiety, epilepsy and memory deficits. This project will also yield information on the possible interactions between alcohol and prescription drugs like Valium with flavonoids consumed in the diet. Already it is known that a flavonoid in grape fruit juice may influence the metabolism of drugs like Valium. This project will be concerned with possible interactions within the brain. The novel mode of action that we have discovered is of significance in terms of our basic understanding of brain function. It could add another dimension to what we already know about the brain as our most complex organ.Read moreRead less
Pathways Of Neurosteroid-mediated Protection Following Compromised Pregnancy And Preterm Birth
Funder
National Health and Medical Research Council
Funding Amount
$565,785.00
Summary
The hormonal environment of pregnancy is essential for normal development of the fetal brain. Levels of key hormones fall following premature birth and are further suppressed if the fetus is small or subjected to stress. This leads developmental problems in infants from the pregnancies. This project will examine effectiveness of replacement and supplementation treatments with critical neurosteroid hormones in reversing the adverse neurological effects of these complications of pregnancy.
Neuroactive Steroids In The Fetal Brain: Role In The Regulation Of Behaviour And Protection Against Hypoxia
Funder
National Health and Medical Research Council
Funding Amount
$65,685.00
Summary
The major breakdown products of the steroid hormone, progesterone, form a group of hormones termed neuroactive steroids. These steroids have major effects on the activity of the brain and influence behaviour in adult subjects. Changes in the production of steroids by the steroid producing glands influences neurosteroid levels in the adult brain. This in tern may cause behavioural and mood changes in adults, leading to conditions such as premenstrual stress and postnatal depression. In fetal life ....The major breakdown products of the steroid hormone, progesterone, form a group of hormones termed neuroactive steroids. These steroids have major effects on the activity of the brain and influence behaviour in adult subjects. Changes in the production of steroids by the steroid producing glands influences neurosteroid levels in the adult brain. This in tern may cause behavioural and mood changes in adults, leading to conditions such as premenstrual stress and postnatal depression. In fetal life, the placenta releases large amounts of these neuroactive steroids and high concentrations of these steroid are found in the fetal circulation. We have shown that these steroids suppress the activity of the fetal brain, suppress arousal and maintain the fetus in a sleep-like state during pregnancy. In this proposal we investigate the hypothesis that cells in the fetal brain modify the neuroactive steroid environment within the brain so as to suppress fetal brain activity further during times of stress and, therefore, protect the brain from damage caused by excessive excitation. These mechanisms may prevent brain injury due to placental insufficiency during pregnancy and asphyxia during birth. The augmentation of these natural processes may form the bases for treatment strategies to provide additional protection for the fetal brain in high-risk pregnancies.Read moreRead less
Essential Protective Role Of Neuroactive Steroids In The Fetal And Neonatal Brain.
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
Brain injury may occur during complicated pregnancies and at birth, as well as in neonates following preterm labour, and is a major problem in neonatal medicine. The consequent nerve cell death leads to ongoing neurological impairment which represents a major cost to the individual and to the community. Neuroactive steroids are hormones related to the steroid hormone progesterone that have been shown to have a major influence on nerve cell activity and nervous transmission. While these hormones ....Brain injury may occur during complicated pregnancies and at birth, as well as in neonates following preterm labour, and is a major problem in neonatal medicine. The consequent nerve cell death leads to ongoing neurological impairment which represents a major cost to the individual and to the community. Neuroactive steroids are hormones related to the steroid hormone progesterone that have been shown to have a major influence on nerve cell activity and nervous transmission. While these hormones influence mood and behaviour in adult subjects, they have an even more important role in the fetus which is exposed to high levels of steroids from the placenta. The fetus is very sensitive to these neuroactive steroids and we have shown that they suppress the activity of the fetal brain so as to maintain the fetus in a sleep-like state during pregnancy. Periods of low oxygen supply (hypoxia) to the fetus may occur during pregnancy, as well as result from asphyxia at birth, and may lead to excessive excitation of nerve cells resulting in nerve cell death. Steroid-induced suppression reduces excitation of nerve cells and results in the fetus being resistant to excessive excitation. In this proposal we investigate the hypothesis that cells in the fetal brain modify the neuroactive steroid environment within the brain so as to suppress fetal brain activity further during times of hypoxic stress and, therefore, further protect the brain from damage caused by excessive excitation. These mechanisms may prevent brain injury due to placental insufficiency during pregnancy, asphyxia during birth and in premature babies. We will investigate whether the supplementation of these processes by administering neuroactive steroids may provide additional nerve protection during high-risk periods during pregnancy. These studies may identify a new as yet unexploited group of natural compounds which may improve infant health without adverse actions on the mother or baby.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
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