Characterisation Of Substance P Antagonists As A Novel Therapeutic Intervention For Use In Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health problem, no effective treatment currently exists. A number of studies have demonstrated that much of the morbidity following TBI is associated with the development of ....Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health problem, no effective treatment currently exists. A number of studies have demonstrated that much of the morbidity following TBI is associated with the development of a secondary injury process that occurs between hours to days after the insult. This delayed progression of injury suggests that appropriate pharmacologic intervention can prevent, or at least attenuate, this secondary injury process with a resultant improvement in outcome. Over the past 15 years, a number of groups, including ours, have been investigating the secondary mechanisms associated with the development of functional deficits after TBI. Our previous studies have demonstrated that decline in brain free magnesium is associated with functional deficits after experimental brain injury, and that magnesium administration after injury can improve outcome. Magnesium is now on clinical trial as a pharmacologic intervention. Recent studies have suggested that magnesium decline facilitates neurogenic inflammation, which has been associated with oedema formation, oxidative damage and cell death. Although a number of neuropeptides have been implicated in this process, it is thought that substance P release is closely associated with these pathophysiological processes. Therefore, inhibiting neuropeptide release, or inhibiting substance P binding, may offer a novel therapeutic approach for the attenuation of oedema and development of neurologic deficits after TBI. This proposal will use a combined biochemical, pharmacologic and behavioural approach to characterise the role of neuropeptides in brain trauma, and attempt to develop a novel therapy for use in clinical trauma.Read moreRead less
Interactions Between Injured Neurons, Astrocytes And Metallothionein
Funder
National Health and Medical Research Council
Funding Amount
$478,067.00
Summary
We have found that the protein, metallothionein, which protects the brain after injury or during neurodegenerative disease acts in a more complex way than previously thought, including a direct action on injured neurons as well as on the originating cell, astrocytes. Elucidating each component of metallothionein action will help us understand how cells interact in the brain after injury, and excitingly, offers an opportunity to develop an enhanced therapeutic strategy based on this protein.
Reinstating Emotion Perception After Brain Damage: An Experimental Approach
Funder
National Health and Medical Research Council
Funding Amount
$338,421.00
Summary
Many people with traumatic brain injury (TBI) cannot recognise emotions in others. This disrupts social behaviour leading to isolation and unemployment. In this project we determine whether: (1) selectively attending to a person's expression improves empathy and emotion recognition; (2) whether mimicking an expression improves recognition of the emotion and; (3) whether poor recognition of emotional tone of voice (prosody) and audiovisual displays is improved by focusing on voice or face alone.
Despite advances in medical management, critical care clinicians continue to search for procedures that will improve outcomes in critically ill patients with haemorrhagic shock (a life-threatening fall in blood pressure). Shock is a consequence of an active process triggered by the brain . The proposed research aims to elucidate the precise sequence of brain events that initiate and maintain shock. We will also evaluate the effects of interventions (designed to ameliorate or reverse shock) on th ....Despite advances in medical management, critical care clinicians continue to search for procedures that will improve outcomes in critically ill patients with haemorrhagic shock (a life-threatening fall in blood pressure). Shock is a consequence of an active process triggered by the brain . The proposed research aims to elucidate the precise sequence of brain events that initiate and maintain shock. We will also evaluate the effects of interventions (designed to ameliorate or reverse shock) on the brain events that drive the shock response. The results of this research will offer, for the first time, a rational basis for devising new methods to reverse or ameliorate shock and potentially improve clinical outcomesRead moreRead less
Organic Brain Damage After Non-fatal Opioid Overdose
Funder
National Health and Medical Research Council
Funding Amount
$244,858.00
Summary
The study will provide the first data on the level and nature of brain damage due to opioid overdose. The extent to which overdose survivors suffer brain damage has important implications for clinical management, particularly in relation to behavioural problems. It will also provide the first data on brain damage and drug treatment performance. Screening of those with an overdose history may lead to specialised management of these individuals with the potential for improved treatment outcome.
The Role Of SPARC In Regeneration And Neurogenesis In The Central Nervous System.
Funder
National Health and Medical Research Council
Funding Amount
$324,870.00
Summary
Stroke is a leading cause of disability in the elderly. Although the brain has built-in mechanisms for repairing itself, these processes are slow and incomplete. We are investigating how these natural repair mechanisms work and how to stimulate them to improve recovery. Our initial results suggest that a protein called SPARC, which is involved in wound healing outside the nervous system, may be able to recruit new nerve cells and blood vessels to damaged brain tissue.
Raised Intracranial Pressure After Trauma: Characterisation And Development Of Pharmacological Interventions
Funder
National Health and Medical Research Council
Funding Amount
$589,788.00
Summary
Raised intracranial pressure (ICP) commonly occurs after traumatic brain injury (TBI) and is thought to be responsible for up to 50% of all mortality, as well as significantly contributing to the persistent neurological deficits in survivors. Few studies have examined the dynamics of raised ICP after TBI, or its effects on brain oxygenation. This study will fully characterize changes in ICP and brain oxygen after TBI and develop novel treatments to control such changes.
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
Characterisation Of Antioxidant Pathways Involving Gpx-1: Implications For Neural Ischemic Reperfusion Injury.
Funder
National Health and Medical Research Council
Funding Amount
$458,250.00
Summary
Neural damage following stroke can be grouped into two stages. The first occurs immediately following the ischemic insult and results in the rapid loss of neural cell viability; the second stage (which usually results in severe neural dysfunction) occurs over many hours following reperfusion. There is however, a window of opportunity shortly following the ischemia-reperfusion where damage to the brain can be minimized if appropriate therapeutic intervention was available. However, our ability to ....Neural damage following stroke can be grouped into two stages. The first occurs immediately following the ischemic insult and results in the rapid loss of neural cell viability; the second stage (which usually results in severe neural dysfunction) occurs over many hours following reperfusion. There is however, a window of opportunity shortly following the ischemia-reperfusion where damage to the brain can be minimized if appropriate therapeutic intervention was available. However, our ability to identify novel targets and devise strategies for the treatment of stroke relies on our understanding of (a) the molecular processes that are initiated following brain ischemia and (b) the delayed molecular events that follow reperfusion and hypoperfusion and result in extensive neuronal loss. A major component that accompanies stroke is the generation of oxidative stress. Reactive oxygen species (ROS) are thought to make a significant contribution to neuronal cell injury and death during both the early and late stages following ischemia. Therefore the molecular pathways that are involved in ROS generation are prime targets for the development of improved therapies. It has already been established by us that the antioxidant enzyme, glutathione peroxidase-1 (Gpx-1) is essential in protecting neurons from ischemic injury-death. A clearer understanding of how Gpx-1 confers this protection in vivo would make an important contribution towards the design of improved treatments. In this proposal, we plan to determine the role of Gpx-1 in an in vivo model of stroke to: (1) demonstrate in a broader sense the functional importance of this antioxidant enzyme in neuronal survival and (2) to demonstrate in a more specific manner, the impact of this enzyme on two signaling molecules, PI3kinase (PI3K) and NFkB (both of which are redox sensitive and play important roles in neuronal cell viability) and their relevance to ischemic cell injury and death.Read moreRead less