Neuropharmacology
Research
Oxidative stress and Neural Injury
The major focus of our laboratory are the mechanisms that underpin the progression of neural injury. The causes of neural injury are multifactorial so our laboratory’s research is focused on the role that oxidative stress and reactive oxygen species (ROS) play in the predisposition and/or progression of neural injury. Rather than serving solely as harmful by-products of aerobic metabolism, it has become apparent that ROS have a much broader role in the regulation and co-ordination of cellular homeostasis. ROS are used to fine-tune cellular signaling and play an important role in the transduction of message along specific signal transduction pathways. In the event of oxidative stress, which is associated with varied human diseases including neurological disorders, the persistent inactivation of signal transduction pathways by ROS may lead to reduced or ablated, sustained or elevated cellular signaling and predispose or otherwise contribute to disease pathology. In understanding how signal transduction systems are regulated by oxidative stress and ROS we can gain a better understanding how new generation therapeutics can target these pathways in the hope to reduce and or prevent neuronal pathology.
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Innate Immunity and Neural Injury
A major new area of research in our laboratory is the role that the innate immune system plays in the progression of neural injury. It is now appreciated that the central nervous system (CNS) does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Activation of the innate immune system is an important component of this inflammatory response. The innate immune system uses a newly discovered family of receptors to transducer its’ signal called the Toll-like receptors (TLRs). The roll that the TLR’s play in the progression and response to neural in jury is an exciting and emerging field of research. The molecular mechanisms that are influenced by the TLRs comprise new targets for therapeutic intervention into acute neurological conditions such as stroke and neurotrauma and chronic neurological diseases such as multiple sclerosis and Parkinsons disease.
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Stroke
Stroke is the leading cause of long-term disability in adults and ranks as the third leading cause of death after heart disease and cancer. Approximately 80% of all strokes suffered are ischemic, resulting from artery occlusion and causing absent perfusion at the core of the infarct and hypoperfusion at the margin of the blood vessels territory (penumbra). The extent of neurological damage following stroke and the severity of the neurological sequelae depend on the viability of the hypoperfused penumbra and also on whether artery occlusion is transient, resulting in reflow (reperfusion). Hypoperfusion and reperfusion is accompanied by the production of reactive oxygen species (ROS) or free radicals at an enhanced rate. In turn, ROS trigger molecular pathways that lead to necrosis, apoptosis and neuroinflammation with subsequent neuronal loss and consequent disability. The devastation of stroke could be greatly ameliorated if therapies were available to salvage these potentially viable neurons. Therefore the molecular pathways that are involved in ROS generation and neuronal cell injury following ischemia are a prime target for the development of improved therapies.
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Traumatic Brain Injury
Traumatic brain injury (TBI) represents the major cause of death in young individuals in industrialised countries. Despite the improvement of neurosurgical procedures as well as critical care management, morbidity and mortality are still high and approximately 25% of these patients remain with permanent disabilities becoming a familiar, social and economic burden for society. A better understanding of events occurring in the brain after traumatic brain injury is essential to identify ways to limit the damage and ultimately improve the outcome. The advent of microarray technology has given the researcher the ability to potentially identify the regulation of thousands of genes and enables a broad assessment of gene changes after traumatic brain injury. With the backing of the Victorian Trauma Foundation we have undertaken a microarray study to determine a temporal profile of gene changes in the brain after TBI. This data is being used to understand the molecular pathways that are changed in the brain after TBI.
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Key References
1. Crack P.J., Taylor J.M., Ali U., Mansell A., Hertzog P.J. NF-kB mediated neuronal cell death in the glutathione peroxidase-1 knockout mouse in response to ischemia-reperfusion injury. Stroke (2006) in press.
2. Mansell A., Smith R, Doyle S., Gray P., Fenner J., Crack P.J., Nicolson S., Hilton D, O’Neill L. and Hertzog P.J. Suppressor of cytokine signaling (SOCS)-1 negatively regulates Toll like receptor signaling by targeting Mal for degradation. Nature Immunology 2006 Feb;7(2):148-55. News and Views, 2006 7(2):123-24.
3. Crack P.J. and Taylor J.M. Reactive oxygen species and the exacerbation of stroke. Free Radical Biology and Medicine, 2005 Jun 1;38(11):1433-44.
4. Taylor J.M., Iannello R.C., Hertzog P.J. and Crack P.J. Diminished Akt phosphorylation in neurons lacking Gpx1 leads to increased susceptibility to oxidative stress-induced cell death. Journal of Neurochemistry 2005; 92(2):283-93.
5. Taylor J.M., *Crack P.J., Gould J.A., Ali U., Hertzog P.J. and Iannello R.C. Akt phosphorylation and NFkB activation are counter-regulated under conditions of oxidative stress. Experimental Cell Research 2004; 300(2): 463-475.
6. Crack P.J., Taylor J.M., de Haan J.B., Kola I., Hertzog P., and Iannello R.C. Glutathione Peroxidase-1 Contributes to the Neuroprotection Seen in the Superoxide Dismutase-1 Transgenic Mouse in Response to Ischemia/Reperfusion Injury. Journal of Cerebral Blood Flow and Metabolism. 2003, 23(1):19-22.
7. Crack P.J., Taylor J.M., Flentjar N.J., deHaan J., Hertzog P., Iannello R.C. and Kola I., Increased Infarct size and Exacerbated Apoptosis in the Glutathione Peroxidase-1 Knockout Mouse Brain in Response to Ischemia/Reperfusion Injury. Journal of Neurochemistry, 2001; 78 (6): 1989-1999.
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