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A Novel Mechanism For Therapeutically Modulating Neurotransmitter-activated Ion Channels
Funder
National Health and Medical Research Council
Funding Amount
$667,529.00
Summary
This project aims to elucidate the mechanisms by which macrocyclic lactones bind to brain ion channel receptors. This will reveal fundamental new insights into the operation of these receptors and will have important implications for the design of novel treatments for a variety of central nervous system disorders.
Inhibitory Neurotransmitter Receptors As Therapeutic Targets For Chronic Pain And Anxiety Disorders
Funder
National Health and Medical Research Council
Funding Amount
$763,409.00
Summary
There are currently few effective long-term treatments for chronic pain and anxiety disorders. Here we propose to develop innovative therapies for both of these debilitating neurological disorders. In addition, we plan to improve our current understanding of how these disorders occur in the first place. This may identify novel potential therapeutic strategies for treating pain, anxiety and a host of other neurological disorders.
Cage Compounds As Blockers Of GABA And Glycine Receptor-channels
Funder
National Health and Medical Research Council
Funding Amount
$519,000.00
Summary
GABA and glycine are the major inhibitory neurotransmitters in the brain and, together with their associated receptors (GABARs and GlyRs), they are responsible for rapid inhibitory neurotransmission. The importance of these receptors in brain function and dysfunction is emphasized by their implication in a number of hereditary and more complex disorders, such as anxiety, epilepsy, dementias, alcoholism and lack of motor control. Many compounds act on these receptor-channels and modulate their fu ....GABA and glycine are the major inhibitory neurotransmitters in the brain and, together with their associated receptors (GABARs and GlyRs), they are responsible for rapid inhibitory neurotransmission. The importance of these receptors in brain function and dysfunction is emphasized by their implication in a number of hereditary and more complex disorders, such as anxiety, epilepsy, dementias, alcoholism and lack of motor control. Many compounds act on these receptor-channels and modulate their function and some of these are used clinically (e.g., anti-anxiolytics, some anaesthetics). Recently, some compounds which inhibit these receptor-channels (typically convulsant drugs) have, in low doses, been shown to enhance learning and memory and to provide some improvement in different senile dementias. Ginkgo biloba extract is used worldwide and has been shown to be effective in the symptomatic treatment of cognitive disorders associated with old age dementia and Alzheimer's disease. Some of the active constituents, the ginkgo compounds, inhibit the GABA and glycine receptors but, importantly for therapeutic activity, are not convulsants. It is suspected that these and related compounds bind within the pore of these receptor-channels to mediate their inhibition, although the data is conflicting and no-one precisely knows how they act. This project aims to directly investigate how the ginkgo compounds, and the related compound picrotoxinin, act on the GABA and glycine receptors, and to determine the site on the protein to which they bind. Furthermore, this project will shed some light on why picrotoxin is a convulsant but the gingko compounds are not. A more thorough understanding of exactly how these compounds work will give us important information on how these receptor-channels work and will lead to the development of better therapeutics, particularly those targeted against old-age dementias and Alzheimers disease.Read moreRead less
Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones receive and process pain-signalling information from the skin ....Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones receive and process pain-signalling information from the skin and internal organs, and receive inputs from descending pathways. This descending input can either inhibit or enhance the activity of SDH neurones and subsequent pain perception. Till now it has been difficult to directly examine how descending pain pathways influence the small SDH neurones in the spinal cord. A new approach, which has been developed in our laboratory, now allows us to record from these very small SDH neurones in the spinal cord of an intact deeply anaesthetized mouse. In addition, our technique allows us to examine the recorded SDH neurone s responses to functionally relevant stimuli (brushing or pinching the hindpaw) as well as its physiology and anatomy. This project will use our new techniques to examine the effects of activating descending brainstem pathways that alter the way painful stimuli are processed in the spinal cord. The effects of altered levels of inhibition in the spinal cord will also be studied by using mice with naturally occurring mutations in their inhibitory glycine receptors. We believe a more complete understanding of pain processing mechanisms will be achieved by examining the role of descending pathways in an intact animal preparation. Such data are essential for the development of drug therapies that can successfully target pain syndromes.Read moreRead less
Molecular Determinants Of Inhibitory Synaptic Function Studied Using Mutant And Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, ....Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, our aim is to use a range of naturally occuring mice mutants, as well as transgenic mice to modulate the receptor levels and so to examine the role of synaptic function and synaptic dynamics. The outcomes of this project will provide fundamental new knnowledge aimed at understanding how communication in the nervous system works and may suggest ways in which modulation of this information flow could be used to treat disorders of brain function.Read moreRead less
The Search For Novel Therapeutic Targets For The Treatment Of Chronic Pain.
Funder
National Health and Medical Research Council
Funding Amount
$425,048.00
Summary
Chronic pain is very common, with one in five Australians suffering long-term pain that is serious enough to cause disability. It is extraordinarily difficult to treat. Medicines used to treat normal pain symptoms are usually ineffective on chronic pain patients because the cause of the pain is different. The aim of this project is to identify new drug targets in the spinal cord that are specific for chronic pain so we can develop new medicines to reverse the symptoms safely and effectively.