Translational Research in Stroke Laboratory

Contact: Neil Spratt

The Translational Research in Stroke laboratory is part of the Priority Research Centre for Brain and Mental Health. We have a current strong focus in stroke neuroprotection, imaging, basic pathophysiology, and regeneration and plasticity. The latter interest builds on Professor Calford’s strong track record in the field of neuronal plasticity in response to injury. We have active collaborations with several members of our own school, other schools within the University, with the clinical stroke research team based at the John Hunter Hospital (of which Dr Spratt is a member), and are a collaborating centre with the National Stroke Research Institute (NSRI), based in Melbourne.

Current Research

  • Neurosteroid Neuroprotection following stroke.  Preliminary evidence suggests that some GABAA receptor active neurosteroids may be neuroprotective following various forms of central nervous system injury. We are currently undertaking a 3 arm, randomised, double blind, placebo-controlled trial of a neurosteroid, versus progesterone, versus vehicle-control, in a hypertensive rat stroke model. This study has been designed applying the best available evidence for preclinical neuroprotective drug development, building on the Stroke Therapy Academic-Industry Round Table (STAIR) criteria, and incorporating the latest evidence from meta-analysis of the animal neuroprotection literature in stroke.
  • Role of Calcium Calmodulin Dependant Protein Kinase II (CaMKII) in neuroprotection after ischaemia (collaboration with Professor John Rostas, Discipline of Biochemistry, and Deputy Dean, Research).
  • Translation of basic science research into clinical rehabilitation treatment for acute stroke (Collaboration with Heidi Janssen & Dr Michael Pollack, Hunter New England Area Health Service; A.Prof. Julie Bernhardt and Dr Janice Collier, National Stroke Research Institute, Melbourne; and part of a larger basic science – rehabilitation collaboration including A.Prof David Howells, National Stroke Research Institute, Melbourne; Dr Malcolm MacLeod, Centre for Clinical Brain Sciences, University of Edinburgh; Prof Michael Nilsson, Center for Brain Repair and Rehabilitation, Göteborg University).
  • Characterisation of cellular responses to hypothermia. This project builds on an existing clinical trial on which Neil Spratt is an investigator. Hypothermia is perhaps the most promising neuroprotective modality from animal studies, and there is evidence of benefit in human brain ischaemia (cardiac arrest), however large-scale clinical trials are yet to be conducted, in part due to the logistical difficulties implementing hypothermia in stroke patients. We are seeking to understand the cellular adaptations underlying hypothermic neuroprotection, in an effort to develop a more widely applicable therapy for stroke patients.
  • Investigation of histological outcome of ischemic penumbra identified by CT brain perfusion imaging. Again building on existing expertise within the local clinical acute stroke research and laboratory teams, we aim to further investigate this exciting and potentially widely available imaging technique which has the potential to improve patient selection for potentially life-saving thrombolytic (clot-busting) therapy soon after stroke.

Stroke Laboratory Gallery

Click on a thumbnail to view the full-size image in a gallery.
Rat middle cerebral artery thread-occlusion stroke model Hypoxic threatened tissue (ischaemic penumbra) that progresses to infarction (white) or is salvaged (blue) after 2 hours focal ischaemia. Arteries (light red) and veins (dark) on the cortical surface. Laboratory Staff Members
 

Laboratory Members

Professor Mike Calford, Deputy Vice-Chancellor Research. Prof Calford was educated at  Monash University (BScHons in Psychology and PhD in Physiology) and  spent time at City College of New York, University Laboratory of  Physiology at Oxford, University of Queensland (13 years), University  of California at Irvine, and the Australian National University. He is a neuroscientist with a primary interest in plasticity of the cerebral cortex after injury or stroke. Using perturbations of sensory cortex in animal models to investigate basic physiological responses, he was one of the first to demonstrate an extensive capacity for reorganization in the adult and to plot its time course. With his colleagues Professor Calford is presently involved in work into the neuroprotectant properties of steroids and is also studying the physiological basis of tinnitus in terms of maladaptive cortical reorganization. Professor Calford was awarded the 1991 Australian Medical Research Award by the Australian Society for Medical Research. He moved to Newcastle in 2000 as Professor of Human Physiology, and was appointed Head of School of Biomedical Sciences in 2002. He was the Pro Vice-Chancellor for Research 2005-2006 and took up his present appointment in May 2006.

Dr Neil Spratt, PhD FRACP, Greater Building Society/Hunter Medical Research Institute Senior Stroke Research Fellow and Conjoint Senior Lecturer. Dr Spratt completed undergraduate medical training at the University of Newcastle, and specialist physician training at Gosford and John Hunter Hospitals. He completed his PhD in the Neuroregeneration Laboratory at the National Stroke Research Institute and University of Melbourne. His thesis was titled “Evaluation of hypoxic markers for the identification of ischaemic penumbra after stroke”, and involved significant modification of the rat thread occlusion model (see publications). He currently combines laboratory-based translational stroke research (brain protection with neurosteroids) with clinical neurology – as a part-time staff specialist and member of the acute stroke and clinical stroke research teams in the Department of Neurology at the John Hunter Hospital. 

Dr Damian McLeod, PhD. Dr McLeod completed a Bachelor of Biomedical Science and honours degree within the School of Biomedical Sciences and Pharmacy at the University of Newcastle. He is a past recipient of the HMRI Emlyn and Jennie Thomas Post-graduate Scholarship for Cardiovascular Research through the School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle. His PhD research investigated the autonomic mechanisms responsible for changes in airway calibre and blood flow to the airways during exercise. This involved application of a sonomicrometry system to small airways in awake sheep at rest and during exercise. The findings may explain the primary neural mechanisms of exercise-induced asthma. He is currently studying mechanisms of hypothermic neuroprotection and the value of CT perfusion imaging to identify salvageable brain soon after stroke.

Ms Debbie-Gai Pepperall, Dip. Path., Research Assistant. Debbie has an impressive track record producing high-quality histological sections for research and clinical applications, and for publications including Wheater’s Functional Histology and Wheater’s Histopathology. She also works part-time at the Wickham TAFE teaching histology techniques. Several of her students have progressed to successful research careers 

Ms Amelia Tomkins, B. Biomed. Sci. – Research Assistant. Amelia Completed her B. Biomed Sci. at the University of Newcastle. She commenced an Honours degree in our laboratory in 2008, focussing on the quantification and localisation of endogenous neurosteroid production following focal ischaemia

Ms Phoebe Chung, M. Sc. – Research assistant. Phoebe commenced work in the translational research in stroke laboratory during 2008. She completed her Masters with a study of myogenic stem cell regeneration, which required the mastery of laser capture microdissection and protein analysis. She subsequently worked in the laboratory of Paul Smith, working on a project to investigate proliferation of neuronal lineage cells within hippocampus following bilateral vestibular lesions.

Selected Publications

  • Calford, M. B., M. L. Graydon, M. F. Huerta, J. H. Kaas and J. D. Pettigrew (1985)  A variant of the mammalian somatotopic map in a bat.  Nature  313:  477-479.
    Calford, M. B. and R. Tweedale  (1988)  Immediate and chronic changes in responses of somatosensory cortex in adult flying-fox after digit amputation.  Nature  332: 446-448.
  • Calford, M.B. and R. Tweedale (1990)  Interhemispheric transfer of plasticity in the cerebral cortex.  Science 249:805-7.
  • Calford M.B. (2002) Dynamic representational plasticity in sensory cortex. Neuroscience 111:709-738.
  • Tailby C, Wright LL, Metha AB, Calford MB. Activity-dependent maintenance and growth of dendrites in adult cortex. Proc Natl Acad Sci U S A. 2005;102:4631-4636
  • Saalmann, Y. B., Kirkcaldie, M. T., Waldron, S., and Calford, M. B. 2007. Cellular distribution of the GABAA receptor-modulating 3alpha-hydroxy, 5alpha-reduced pregnane steroids in the adult rat brain. J Neuroendocrinol 19: 272-284.
  • Spratt, N. J., J. Fernandez, M. Chen, S. Rewell, S. Cox, L. Van Raay, L. Hogan and D. W. Howells (2006). Modification of the Method of Thread Manufacture Improves Stroke Induction Rate and Reduces Mortality after Thread-Occlusion of the Middle Cerebral Artery in Young or Aged Rats. Journal of Neuroscience Methods 155:285-290
  • Spratt NJ, Ackerman U, Tochon-Danguy HJ, Donnan GA, Howells DW. (2006). Characterisation of fluoromisonidazole binding in stroke. Stroke 37:1862-7
    Spratt, NJ., Howells DW, Donnan, G. (2007). Imaging the Penumbra: PET FMISO. The Ischaemic Penumbra: History, Current Status and Implications for Therapy. G. Donnan, J. C. Baron, S. Davis and F. R. Sharp. New York, Taylor and Francies Books Inc