Metabotropic Glutamate Receptors: Pharmacological Studies Of Receptor Subtypes In Neuronal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$145,770.00
Summary
Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexp ....Glutamate is the major transmitter of excitatory information in the mammalian brain. Disruption of glutamate-mediated signaling between brain cells results in high extracellular levels of glutamate which is toxic to neurones. A recently discovered family of signal transducers, the metabotropic glutamate receptors, has been found to be localized on neurones and is switched on by these toxic glutamate levels. The roles of these metabotropic glutamate receptors in neurotoxicity is essentially unexplored and is the topic under investigation in this project. How their activation affects cellular signaling switch on will be investigated to gain an understanding of the roles metabotropic glutamate receptors play in acute brain injury (eg stroke) and chronic neurodegenerative conditions (eg Huntington's chorea and Alzheimer's disease).Read moreRead less
The Sulphate Anion Protects Against Stroke: Characterisation Of Neuroprotective Potential And Mechanism Of Action.
Funder
National Health and Medical Research Council
Funding Amount
$189,170.00
Summary
Stroke-cerebral ischaemia affects approximately 40,000 - 50,000 Australians every year and is Australia's leading single cause of disability and second greatest cause of death after heart disease. About 25% of people who suffer a stroke die within one month while most survivors are disabled because of impaired speech, memory, thought processes, vision, balance, or motor control of the limbs (paralysis). The direct and indirect cost of stroke to the Australian community is over $2 billion annuall ....Stroke-cerebral ischaemia affects approximately 40,000 - 50,000 Australians every year and is Australia's leading single cause of disability and second greatest cause of death after heart disease. About 25% of people who suffer a stroke die within one month while most survivors are disabled because of impaired speech, memory, thought processes, vision, balance, or motor control of the limbs (paralysis). The direct and indirect cost of stroke to the Australian community is over $2 billion annually. Hence preventing or reducing brain damage following stroke is of fundamental clinical, social and economic significance. A stroke occurs when there is a reduced blood supply to the entire brain (Global ischaemia; eg. cardiac arrest, heart bypass surgery, closed head injury) or when there is a reduced blood supply to a specific region of the brain, usually as a result of a blockage in a brain artery (thrombo-embolic stroke or focal ischaemia). Despite decades of research, there is no totally satisfactory clinical treatment to reduce brain damage following stroke; the search for new treatments is paramount. We have shown that sodium sulphate can prevent brain damage in rat models of focal and global ischaemia. Importantly we demonstrated that sodium sulphate could prevent brain damage when given up to 8 hours after the stroke was induced in the global model. Delayed treatment following stroke is of clinical significance, since most patients do not receive medical attention until several hours after initial stroke symptoms. It is not known how sodium sulphate protects the brain from stroke. This project has three main aims: 1. To determine the how well sodium sulphate treatment protects the brain in rats following stroke. 2. To determine if sodium sulphate treatment can reduce brain damage in the rat model of focal ischaemia when given 4 - 8 hours after the stroke. 3. To determine how sodium sulphate protects the brain from stroke.Read moreRead less
Pharmacological Strategies To Prevent Damage To White Matter In The Central Nervous System After Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$150,770.00
Summary
A stroke is caused by an acute blockade of blood flow to a brain region and in most cases, is caused by a clot in the artery that supplies the oxygenated blood and nutrients such as glucose to that region. Within minutes, the region of the brain that is deprived of blood flow will die and so the functions controlled by that region are lost. In the majority of stroke patients, the middle cerebral artery is blocked and this affects parts of the brain controlling movement of limbs or speech and so ....A stroke is caused by an acute blockade of blood flow to a brain region and in most cases, is caused by a clot in the artery that supplies the oxygenated blood and nutrients such as glucose to that region. Within minutes, the region of the brain that is deprived of blood flow will die and so the functions controlled by that region are lost. In the majority of stroke patients, the middle cerebral artery is blocked and this affects parts of the brain controlling movement of limbs or speech and so these patients suffer permanent disabilities. Not surprisingly, stroke is the most common life-threatening neurological disease and the major cause of disbility in adults over 45 years of age. Apart from the profound effect that stroke has on the patient and family, the annual cost of disability to the Australian community is approximately $ 1 billion. If the disability could be reduced, this could reduce the need for institutionalisation of patients and then the cost saving would be great. So our research is directed towards designing drugs to minimise the disability after stroke. Research in the past has focussed on designing drugs to minimise damage to the grey matter in brain but it is becoming apparent that the white matter in brain is very important for transmitting information and also needs to be protected. We will study the biochemical changes in white matter after a stroke in a rat model and use this information to design in a rational way, novel drugs to minimise damage to white matter (axons), thereby reducing the degree of disability after a stroke.Read moreRead less
Arachidonic Acid Modulation Of Glutamate Transporters
Funder
National Health and Medical Research Council
Funding Amount
$286,980.00
Summary
Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also fo ....Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also for long term neurological disorders such as Alzheimer's disease. In this project we shall investigate a novel mechanism for regulating the activity of glutamate transporters and explore the possibility of pharmacologically manipulating glutamate transporters. This work may lead to the development of novel compounds that improve transporter function and reduce the pathological consequences of impaired transporter function. Such compounds may have therapeutic potential as neuroprotectants in the treatment of neurological disorders such ischaemic brain damage or neurodegenerative disorders such Alzheimer's disease.Read moreRead less
Characterisation Of A Novel Direct Electrochemical Chip As A Biosensor And Tool For Studying Redox-sensitive Proteins
Funder
National Health and Medical Research Council
Funding Amount
$144,500.00
Summary
Biosensors use biomolecules to detect a chemical event. They are becoming important for the rapid and reliable measurement of the concentrations of molecules in fluids. In human medicine they will be of great use to general practitioners and patients for instantaneous read outs of concentrations of many different biological molecules. How well a biosensor responds depends on the method in which the biomolecule is immobilised to a surface and the signal detected. We have made a significant advanc ....Biosensors use biomolecules to detect a chemical event. They are becoming important for the rapid and reliable measurement of the concentrations of molecules in fluids. In human medicine they will be of great use to general practitioners and patients for instantaneous read outs of concentrations of many different biological molecules. How well a biosensor responds depends on the method in which the biomolecule is immobilised to a surface and the signal detected. We have made a significant advance in biosensing capabilities using a recombinant protein (thioredoxin) and demonstrated the improvement that is possible by (i) immobilising the protein in a highly oriented way and (ii) using a sensitive electrical signal to monitor the response. Here we will undertake more comprehensive testing by extending the number of proteins to include the 4 major classes of redox-sensitive biomolecules (proteins) in the body. This will enable us to establish the broad application of our methods and substantially improve our ability to commercialize our discoveries.Read moreRead less