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
Given that consumption of flavonoids in the diet is likely to be 100-1000 mg per day, it is important to find out how flavonoids might influence GABA-A receptors especially in relation to influencing actions of other therapeutic agents that interact with GABA-A receptors in the brain, such as benzodiazepines and ethanol. This may lead to new strategies in the use of herbal medicines and their possible interactions with other medications. These studies will provide information on how key dietary ....Given that consumption of flavonoids in the diet is likely to be 100-1000 mg per day, it is important to find out how flavonoids might influence GABA-A receptors especially in relation to influencing actions of other therapeutic agents that interact with GABA-A receptors in the brain, such as benzodiazepines and ethanol. This may lead to new strategies in the use of herbal medicines and their possible interactions with other medications. These studies will provide information on how key dietary flavonoids and novel structurally related chemicals could influence brain function. This project will probe the chemical characteristics of novel modes of action of flavonoid-related compounds in order to design and develop potentially useful therapeutic agents for CNS disorders involving GABA-A receptors. It is likely that flavonoids act on specific sites on such receptors that represent important new targets for drug development. This research is intended to provide new chemical entities useful as either alternatives to the benzodiazepines, which have a range of undesirable side effects, or as adjuncts to enable reduced doses of benzodiazepines to be used.Read moreRead less
Effects Of Mutations In The Conserved Cysteine Loop Of The GABA-A Receptor
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general ....Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. Leading, currently used general anaesthetics, anxiolytic and anti-epileptic drugs act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered serendipitously. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. Specific mutations in GABA-A receptors can have a profound influence on their function. Studying the effects of mutations is slowly giving us more information about the ion channel region and drug binding sites. Recently, mutations in GABA-A receptors have been found to be associated with some forms of epilepsy. In this project, we plan to examine the effects of mutations in highly conserved residues of a small region of subunits of the GABAA receptor because: (1) we (and others) have preliminary evidence that this loop forms a connection between the GABA binding site and the ion channel and (2) we think that this part of the receptor is vital for the effects of some drugs.Read moreRead less
Substances that enhance the action of the inhibitory neurotransmitter GABA in the brain are amongst the most widely used drugs. They include many anaesthetics, anxiolytics and sedatives. Their enhancing action is mediated by increasing the effectiveness of GABA acting on GABA receptors, in particular the subtype of GABA receptors known as GABA-A receptors. This action, termed positive modulation, is poorly understood in molecular terms. Our discovery of second order modulators that only act in c ....Substances that enhance the action of the inhibitory neurotransmitter GABA in the brain are amongst the most widely used drugs. They include many anaesthetics, anxiolytics and sedatives. Their enhancing action is mediated by increasing the effectiveness of GABA acting on GABA receptors, in particular the subtype of GABA receptors known as GABA-A receptors. This action, termed positive modulation, is poorly understood in molecular terms. Our discovery of second order modulators that only act in conjunction with first order modulators adds an exciting new dimension to the concept of influencing the ways in which GABA receptors can be modulated. This offers a new approach to the development of therapeutic agents acting on GABA receptors and thus the treatement of important disorders such as anxiety, epilepsy and insomnia.Read moreRead less
Structural Determinants Underlying High Conductance GABA-A Channels
Funder
National Health and Medical Research Council
Funding Amount
$364,080.00
Summary
Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effec ....Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. The leading general anaesthetics, anxiolytic and anti-epileptic drugs currently used, act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered by serendipity. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. In this project we plan to examine what the functional consequences are and how GABA-A receptors colocalise in the membrane, akin to their physical state in the brain. We will examine the effects of drugs on receptors colocalised in the membrane. We have preliminary evidence suggesting that when GABA-A receptors are close to each other they open together so that their inhibitory response is maximised. Drugs are also able to make GABA-A receptors open in concert. The concept that receptors in the membrane talk to each other has been shown to occur for receptors from different classes but we now have evidence that the same type of receptors i.e. GABA-A receptors, are able to talk to each other.Read moreRead less
Extrasynaptic GABA-A Receptors As Novel Targets For -Hydroxybutyric Acid (GHB)
Funder
National Health and Medical Research Council
Funding Amount
$525,946.00
Summary
GHB (known as Fantasy) is a curious substance. It is a drug of abuse, a therapy and occurs naturally in the brain. GHB targets brain proteins including the enigmatic _GHB receptor� which participates in the therapeutic benefits of GHB. Our research will determine whether the delta-containing GABA-A receptors are the elusive "GHB receptor". Uncovering the identity of the the elusive _GHB receptor� would be a major breakthrough in terms of our understanding of the therapeutic and recreational use ....GHB (known as Fantasy) is a curious substance. It is a drug of abuse, a therapy and occurs naturally in the brain. GHB targets brain proteins including the enigmatic _GHB receptor� which participates in the therapeutic benefits of GHB. Our research will determine whether the delta-containing GABA-A receptors are the elusive "GHB receptor". Uncovering the identity of the the elusive _GHB receptor� would be a major breakthrough in terms of our understanding of the therapeutic and recreational use of GHB and its action as a brain chemical.Read moreRead less
Mechanisms Underlying Generation Of Febrile Seizures In Mouse Models Of Human Familial Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$304,559.00
Summary
Febrile Seizures (FS) affect 3% of children aged 0.5 - 6 yrs and have been proposed as an indicator of severe forms of adult generalized epilepsy. Mechanisms underlying FS generation are unknown although studies of Australian families suffering from epilepsy have linked 2 genes to FS. We have generated mice expressing these 2 genes. Aims and Outcomes: to investigate events triggering FS which will provide important insights into why FS occurs in children. (NB: CIA 2 yr career interruption)