Dr Chris McCabe
- Research Fellow (Stroke and Brain Imaging)
Stroke is the third leading cause of death in the UK and a leading cause of disability. With an ageing population the burden of stroke will only increase since age is the single most important non-modifiable risk factor for the development of stroke. Ischaemic stroke accounts for approximately 85% of all strokes and is caused by an occlusion of a blood vessel in the brain. This can be through an atherosclerotic plaque, thrombus, or emboli. The ‘ischaemic penumbra’ is a region of hypoperfused brain tissue that is metabolically active and, importantly, potentially salvageable if early restoration of blood flow is induced. This penumbral tissue will become incorporated into the irreversibly damaged infarct over time if blood flow is not restored quickly enough with brain cells dying every minute. The only licenced pharmacological treatment for acute ischaemic stroke is recombinant tissue plasminogen activator (rt-PA) which acts to recanalise the occluded blood vessel and reperfuse brain tissue. However, this treatment is only licenced to be given within the first 4.5 hours after stroke onset. Therefore, there is an urgent need to develop new treatments that act to protect brain tissue and improve regeneration following stroke.
My research group is interested in understanding the mechanisms of brain damage during the acute phase following stroke (critical first hours) particularly in animal models that display known stroke co-morbidities (i.e hypertension, gender, hyperglycaemia). We are investigating novel approaches to protect the brain and vasculature following stroke with the aim of protecting the ischaemic penumbra and promoting regeneration. We use a range of in vivo research techniques such as MRI, laser Doppler flowmetry, laser speckle contrast imaging, and in vivo autoradiography as well as ex-vivo techniques such as histology, western blotting, and PCR.
A list of some of our specific research themes are outlined below.
1. Evolution of the Ischaemic Penumbra: Influence of Stroke Co-Morbidities
We use MRI to track the evolution of ischaemic damage following stroke (diffusion weighted imaging, perfusion weighted imaging, T2 weighted imaging etc), particularly during the acute phase, allowing us to follow the lifespan of potentially salvageable tissue (ischaemic penumbra). We have demonstrated differences in outcome in hypertensive vs. normotensive rats with greater ischaemic damage from as early as 30 minutes post stroke and less penumbral tissue (McCabe et al., 2009; Reid et al., 2012). Similarly, we have shown that gender influences outcome during the acute phase following stroke with females having significantly less ischaemic damage than males during the first 4 hours after stroke onset (Baskerville et al., 2015).
Collaborators: Professor I. Mhairi Macrae, Dr William Holmes, Dr Deborah Dewar, and Dr Emma Reid (Institute of Neuroscience and Psychology).
2. Understanding the Role of the Angiotensin-(1-7) Following Stroke
The renin angiotensin system (RAS), is crucial in the control of blood pressure regulation and volume homeostasis. Angiotensin-(1-7), a biologically active peptide of the RAS, counteracts the damaging effects of Angiotensin II as well as having direct beneficial effects through its actions at the Mas receptor. There has been increasing interest into the role of Angiotensin-(1-7) in stroke due to its vasodilator, anti-oxidant, and anti-inflammatory properties.
Our group is investigating the role of Angiotensin-(1-7) during both acute and long-term recovery from stroke using pertinent animal models displaying known stroke co-morbidities (hypertension, gender). We are investigating the role of Angiotensin-(1-7) during the first critical hours following stroke in order to determine whether treatment can improve collateral blood flow therefore increasing and/or prolonging the duration of the ischaemic penumbra and increasing tissue salvage following stroke.
Collaborators: Dr Stuart Nicklin and Dr Lorraine Work (Institute of Cardiovascular and Medical Sciences), and Dr Emma Reid (Institute of Neuroscience and Psychology).
3. Inhaled Nitric Oxide for the Treatment of Stroke
Inhalation of nitric oxide (NO) is a potent vasodilator that has approval for the treatment of persistent pulmonary hypertension in newborns. The vasodilator actions of inhaled NO extend beyond the pulmonary circulation with effects shown in other vascular beds. Recent studies have demonstrated that inhaled NO can protect the brain following experimental stroke and traumatic brain injury and that these effects may be mediated through improved blood flow to the brain. We are working on understanding the effects of inhalation of NO on the CBF response following acute ischaemic stroke and in particular its effect in the presence of known stroke risk factors.
Collaborators: Professor I. Mhairi Macrae (Institute of Neuroscience and Psychology).
4. Investigating the Role of Integrins on Blood Brain Barrier Permeability and Outcome Following Stroke
The extracellular matrix comprises 10-20% of total brain volume and is made up of proteins and glycans that act to provide structural support and organisation of neurons and glia. In addition, it provides signalling for cell growth, survival, maintenance of the blood brain barrier, and neural activity. Cerebral ischaemia results in rapid proteolysis of the extracellular matrix releasing biologically active matrix fragments such as proteoglycans. Integrins are transmembrane adhesion receptors that act to bind cells to the extracellular matrix. They have an intrinsic role in maintaining the integrity of the blood brain barrier. We are investigating the role of specific integrins following stroke in collaboration with Professor Greg Bix (University of Kentucky).
Collaborators: Professor Greg J. Bix (University of Kentucky) and Professor I. Mhairi Macrae (Institute of Neuroscience and Psychology).
5. Impact of Circadian Desynchrony on Outcome Following Stroke
Circadian rhythms are physiological and behavioural changes that display a cyclical change over a 24 hour period. In humans, circadian physiological rhythms are controlled by the ‘master clock’ located within the suprachiasmatic nucleus of the hypothalamus. Disturbances of these circadian rhythms can occur in people who work irregular shifts (i.e shiftworkers) or in jet lag and have been associated with an increased risk of metabolic disease such as insulin resistance, obesity and hypertension. We are interested in the impact of disruption of circadian rhythms on sensitivity to experimental stroke and cerebrovascular response.
Collaborators: Dr Deborah Dewar (Institute of Neuroscience and Psychology), Dr Cathy Wyse (Institute of Biodiversity , Animal Health, and Comparitive Medicine), and Professor Stephany Biello (Institute of Neuroscience and Psychology).
Grants and Awards listed are those received whilst working with the University of Glasgow.
- Memantine - developing a prophylactic treatment for ischaemic stroke.
The Henry Smith Charity
2016 - 2017
- Angiotensin-(1-7): a novel treatment for acute and long term recovery from stroke?
The Henry Smith Charity
2014 - 2016
- Supporting the ischaemic brain with oxygen-carrying perfluorocarbons.
Chief Scientist Office
2012 - 2015
- Sodium imaging following an "Oxygen Challenge" to assess function of the N/K ATP pump following ischaemia to demonstrate membrane integrity: A novel technique to identify the functional "Penumbra"?
2011 - 2012
- Development and application of oscillatory gradient spin echo in stroke animal model at 7T and further validation with histology
2011 - 2014
- Inhibition of NADPH Oxidase as a potential neuroprotective strategy in the Sstroke Prone Spontaneously Hypertensive (SHRSHP) rat
2010 - 2011
- Metabolic syndrome, hyperglycemia and experimental stroke
Scottish Executive Health Department
2009 - 2010
- Development and Validation of an MRI Method to Image Cerebral Metabolism using Oxygen 17.
2009 - 2009
- Assessment of Myoglobin as a Novel MR Reporter Gene and its potential to protect Embryonic Stem Cells against hypoxia
2009 - 2010
- Imaging the ischaemic penumbra using BOLD MRI with oxygen challenge as a biotracer
Medical Research Council
2008 - 2011
- Characterising the ischaemic penumbra in the SIIRSP and WKY following focal cerebral ischaemia
2006 - 2007