Florey Department of Neuroscience and Mental Health - Research Publications
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ItemDiacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-12-23)Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
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ItemThe Minimal Active Structure of Human Relaxin-2(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-10-28)H2 relaxin is a peptide hormone associated with a number of therapeutically relevant physiological effects, including regulation of collagen metabolism and multiple vascular control pathways. It is currently in phase III clinical trials for the treatment of acute heart failure due to its ability to induce vasodilation and influence renal function. It comprises 53 amino acids and is characterized by two separate polypeptide chains (A-B) that are cross-linked by three disulfide bonds. This size and complex structure represents a considerable challenge for the chemical synthesis of H2 relaxin, a major limiting factor for the exploration of modifications and derivatizations of this peptide, to optimize effect and drug-like characteristics. To address this issue, we describe the solid phase peptide synthesis and structural and functional evaluation of 24 analogues of H2 relaxin with truncations at the termini of its peptide chains. We show that it is possible to significantly truncate both the N and C termini of the B-chain while still retaining potent biological activity. This suggests that these regions are not critical for interactions with the H2 relaxin receptor, RXFP1. In contrast, truncations do reduce the activity of H2 relaxin for the related receptor RXFP2 by improving RXFP1 selectivity. In addition to new mechanistic insights into the function of H2 relaxin, this study identifies a critical active core with 38 amino acids. This minimized core shows similar antifibrotic activity as native H2 relaxin when tested in human BJ3 cells and thus represents an attractive receptor-selective lead for the development of novel relaxin therapeutics.
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ItemCellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-03-11)The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
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ItemNo Preview AvailableGenetics of Atrial Fibrillation and Possible Implications for Ischemic Stroke(HINDAWI LTD, 2011)Atrial fibrillation is the most common cardiac arrhythmia mainly caused by valvular, ischemic, hypertensive, and myopathic heart disease. Atrial fibrillation can occur in families suggesting a genetic background especially in younger subjects. Additionally recent studies have identified common genetic variants to be associated with atrial fibrillation in the general population. This cardiac arrhythmia has important public health implications because of its main complications: congestive heart failure and ischemic stroke. Since atrial fibrillation can result in ischemic stroke, one might assume that genetic determinants of this cardiac arrhythmia are also implicated in cerebrovascular disease. Ischemic stroke is a multifactorial, complex disease where multiple environmental and genetic factors interact. Whether genetic variants associated with a risk factor for ischemic stroke also increase the risk of a particular vascular endpoint still needs to be confirmed in many cases. Here we review the current knowledge on the genetic background of atrial fibrillation and the consequences for cerebrovascular disease.
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ItemNo Preview AvailableDemographic and stroke-related factors as predictors of quality of acute stroke care provided by allied health professionals(DOVE MEDICAL PRESS LTD, 2011)BACKGROUND: We recently indicated that patient age on its own is not a determinant of quality of allied health care received after an acute stroke. It has not been tested whether other non-age variables influence care decisions made by allied health professionals. This paper explores demographic and stroke-related variables that are putatively associated with the quality of care provided to acute stroke patients by allied health professionals. METHODS: Data were retrospectively audited from 300 acute stroke patient records regarding allied health care. Compliance with each of 20 indicators of allied health care quality was established. The influence of various demographic and stroke-related variables on each performance indicator was examined. We undertook a series of analyses using univariate logistic regression models to establish the influence of these variables on care quality. RESULTS: Patient age had a significant correlation with only one process indicator (early mobilization). Seven variables, including stroke severity and level of dependence, were associated with patient age. The majority of these age proxies had significant associations with process indicator compliance. Correlations between non-age variables, in particular stroke severity and comorbidity, suggest the potential for complex confounding relationships between non-age variables and quality of allied health care. CONCLUSION: Compliance with individual indicators of allied health care was significantly associated with variables other than patient age, and included stroke severity, previous independence, comorbidities, day of admission, stroke unit admission, and length of stay. The inter-relationships between these non-age variables suggest that their influence on quality of care is complex.
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ItemNo Preview AvailableDoes evidence really matter? Professionals' opinions on the practice of early mobilization after stroke(DOVE MEDICAL PRESS LTD, 2011)INTRODUCTION: Early mobilization after stroke may be important for a good outcome and it is currently recommended in a range of international guidelines. The evidence base, however, is limited and clear definitions of what constitutes early mobilization are lacking. AIMS: To explore stroke care professionals' opinions about (1) when after stroke, first mobilization should take place, (2) whether early mobilization may affect patients' final outcome, and (3) what level of evidence they require to be convinced that early mobilization is beneficial. METHODS: A nine-item questionnaire was used to interview stroke care professionals during a conference in Sydney, Australia. RESULTS: Among 202 professionals interviewed, 40% were in favor of mobilizing both ischemic and hemorrhagic stroke patients within 24 hours of stroke onset. There was no clear agreement about the optimal time point beyond 24 hours. Most professionals thought that patients' final motor outcome (76%), cognitive outcome (57%), and risk of depression (75%) depends on being mobilized early. Only 19% required a large randomized controlled trial or a systematic review to be convinced of benefit. CONCLUSION: The spread in opinion reflects the absence of clear guidelines and knowledge in this important area of stroke recovery and rehabilitation, which suggests further research is required.
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ItemNo Preview AvailableAge and gender as predictors of allied health quality stroke care(DOVE MEDICAL PRESS LTD, 2011)BACKGROUND: Improvement in acute stroke care requires the identification of variables which may influence care quality. The nature and impact of demographic and stroke-related variables on care quality provided by allied health (AH) professionals is unknown. AIMS: Our research explores the association of age and gender on an index of acute stroke care quality provided by AH professionals. METHODS: A retrospective clinical audit of 300 acute stroke patients extracted data on AH care, patients' age and gender. AH care quality was determined by the summed compliance with 20 predetermined process indicators. Our analysis explored relationships between this index of quality, age, and gender. Age was considered in different ways (as a continuous variable, and in different categories). It was correlated with care quality, using gender-specific linear and logistic regression models. Gender was then considered as a confounder in an overall model. RESULTS: No significant association was found for any treatment of age and the index of AH care quality. There were no differences in gender-specific models, and gender did not significantly adjust the age association with care quality. CONCLUSION: Age and gender were not predictors of the quality of care provided to acute stroke patients by AH professionals.
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ItemNo Preview AvailableAlzheimer's disease and metals: a review of the involvement of cellular membrane receptors in metallosignalling.(Hindawi Limited, 2011-03-02)Alzheimer's disease (AD) is a debilitating form of dementia. The hallmark protein associated with the disease is the amyloid beta (Aβ) peptide. Aggregation of Aβ has been shown to depend on interactions with metals. The recent studies now demonstrate that metals also play additional important roles in the disease process. Consequently, there may be benefit from modulating metal homeostasis. However, the role and subcellular location of metals within neurons is not well understood. There is growing evidence to suggest that metals can act at the site of cellular membrane receptors and affect cellular signaling by modulating the signal transduction of those receptors. The glutamatergic and cholinergic receptor systems, both well-known neurotransmitter systems affected in AD, have well-documented metal interactions, as do the tropomyosin-receptor kinase (Trk) family of receptors and the epidermal growth factor (EGF) receptor. In this paper, the metal interactions with these membrane receptor systems will be explored and thus the potential for membrane receptors as an intervention point in AD will be assessed.
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ItemNo Preview AvailableFunctional Integration of Grafted Neural Stem Cell-Derived Dopaminergic Neurons Monitored by Optogenetics in an In Vitro Parkinson Model(PUBLIC LIBRARY SCIENCE, 2011-03-04)Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.
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ItemEvaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk(NATURE PUBLISHING GROUP, 2011-12-06)BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.