Andrew David Greenhalgh

Andrew David Greenhalgh

AgreenSkills session, year: 1st session, 2016

Receiving laboratory: NutriNeuro Nutrition and integrated neurobiology, Bordeaux, Aquitaine

Country of origin : Canada




Mobility project

N-3 polyunsaturated fatty acids (PUFAs) as a novel protective strategy against the cumulative damage of repetitive mild traumatic brain injury (TBI)

Traumatic brain injury is a major public health issue and represents the leading cause of disability and death among young adults and children in Europe. Repetitive mild TBI (rmTBI) is a particularly dangerous form of brain injury, due to both its prevalence and limited overt clinical signs. This is concerning as rmTBI can lead to cumulative injury and is an established risk factor for dementia. Despite this, little is known about the mechanisms driving the cumulative detrimental effects rmTBI, and there is a pressing need to develop novel interventional strategies. Inflammatory processes are closely linked to brain injury. It is now understood that nutrition and, n-3 PUFAs in the diet can prevent the harmful effects of brain inflammation and promote repair. Microglial are key mediators of brain inflammation but the way this inflammation resolves after mTBI, before a second injury, has received little attention. We hypothesise that unresolved inflammatory responses play a key role in the cumulative damage of rmTBI and these can be modulated by the administration of n-3 PUFAs, to reduce the harmful, cumulative effects of a second injury. We will take a system’s biology approach in relevant mouse model of rmTBI and evaluate multiple parameters of microglia-mediated inflammation in the critical time period between two injuries. Genomic and lipidomic screens will provide new mechanistic insights for rmTBI treatments. We will then modulate these inflammatory processes through administration of n-3 PUFAs and evaluate behavioural outcomes and assess early signs of neurodegeneration to validate n-3 PUFAs as a clinical candidate for use in rmTBI.

Biography & research interests

2011-2016 Postdoctoral Fellow – Dr Sam David’s Lab, McGill University, Montreal, Canada.
2007-2007 PhD Neuroscience – Prof. Dame Nancy Rothwell’s Lab, University of Manchester, UK.
2003 – 2007 BSc (Hons) Psychology & Neuroscience University of Manchester, UK.
My fundamental research interest is the immune system’s role in central nervous system (CNS) injury and disease. More specifically, the role of inflammation after acute CNS injury. Whether CNS injury is ischaemic, inflammatory, autoimmune or traumatic, each insult carries common and context-dependent responses which shape CNS recovery. My research aim is to provide solid, mechanistic understanding of CNS injury. During my PhD training in the UK, my major contribution to the field was to provide preclinical data to support the investigation of the anti-inflammatory drug, interleukin-1 receptor antagonist (IL-1Ra) for the treatment of human stroke and subarachnoid haemorrhage (SAH). These data have helped IL-1Ra reach phase III clinical trials for SAH. During my postdoctoral work at McGill University, I began to investigate the response of the cellular elements involved in the inflammatory response of CNS injury; microglia and macrophages. Following this, we have identified key inflammatory mechanisms after SCI and novel interactions of immune cells in the CNS. My work going forward will be to use this knowledge and integrate dietary manipulations into treating the injured CNS.

Selected publications

Greenhalgh AD, Passos dos Santos R, Zarruk JG, Salmon CK, Kroner A, David S (2016). Arginase-1 is Expressed Exclusively by Infiltrating Myeloid Cells in CNS Injury and Disease. Brain Behav Immun ;56: 61-7.

Lewitus GM*, Konefal SC*, Greenhalgh AD, Pribiag H, Augereau K and Stellwagen D (2016). Microglial TNFα suppresses cocaine-induced plasticity and behavioral sensitization. Neuron. May 4;90(3):483-9 *authors contributed equally.

# Anderson, WD, Makadia HK, Greenhalgh AD, Schwaber J, David S, Vadigepalli R (2015) Computational modeling of cytokine signaling in microglia. Mol BioSyst, Dec;11(12):3332-46.

David S, Greenhalgh AD, Kroner A (2015). Macrophage and Microglial Plasticity in the Injured Spinal Cord. Neuroscience 307:311-8.

# Giles JA*, Greenhalgh AD*, Davies CL, Denes A, Shaw T, Coutts G, Rothwell NJ, McColl BW, Allan SM (2015). Requirement for interleukin-1 to drive brain inflammation reveals tissue-specific mechanisms of innate immunity. Eur J Immunol. Feb; 45(2):525-30. *authors contributed equally.
# Kroner A, Greenhalgh AD, Zarruk JG, Passos Dos Santos R, Gaestel M, David S (2014). TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron. Sep 3; 83(5):1098-116.

# Greenhalgh AD, David S (2014). Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death. J Neurosci. Apr 30;34(18):6316-22.

Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A, Cawthorne C, Julyan P, Wilkinson SM, Banister SD, Brown G, Herholz K, Kassiou M, Rothwell NJ (2013) [18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats.. PLoS One;8(2): e56441.

Zusso M, Methot L, Lo R, Greenhalgh AD, David S, Stifani S (2012). Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor runx1. Journal of Neuroscience. 15; 32(33):11285-98.

Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ, Allan SM (2012) Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J Cereb Blood Flow Metab. 32 (9):1810-9.

Greenhalgh AD, Brough D, Robinson EM, Girard S, Rothwell NJ, Allan SM (2012) Interleukin-1 receptor antagonist is beneficial in rat subarachnoid haemorrhage by blocking haem driven inflammation. Disease Models & Mechanisms 6:823-33.

Greenhalgh AD, Rothwell NJ & Allan SM (2012) An endovascular perforation model of subarachnoid haemorrhage in rat produces heterogeneous infarcts that increase with blood load. Translational Stroke Research 3:164–172.

David S, Greenhalgh AD, López-Vales R (2012) Role of Phospholipase A2s and Lipid Mediators in Secondary Damage after Spinal Cord Injury. Cell and Tissue Research. 349(1):249-67.

Greenhalgh AD, Ogunbenro K, Rothwell NJ, Galea J (2011) Translational pharmacokinetics: challenges of an emerging approach to drug development in stroke. Exp Opin in Drug Metab Toxicol 7(6):681-95.

Greenhalgh AD, Galea J, Denes A, Tyrrell PJ, Rothwell NJ (2010) Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection. Br J of Pharmacol 160: 153-159.

Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ (2010) Platelet interleukin-1α drives cerebrovascular inflammation. Blood 115: 3632-3639.

Galea J, Ogungbenro K, Hulme S, Greenhalgh A, et al., (2010) Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study. J Cereb Blood Flow Metab: 31(2):439-47.
Book Chapters

Kroner, A., Greenhalgh, A.D. and David, S. (2014) Microglia and Macrophage Responses and their Role after Spinal cord Injury. In: Neuroinflammation: “New Insights into Detrimental and Beneficial functions”. (S. David, Editor), Wiley Press.

Awards & patents

2013: Canadian Institute for Health Research (CIHR) Postdoctoral Fellowship – $135,000 / 3yrs.
2011: Neuroinflammation CIHR Strategic Training Program Award – $40,000 / 2yrs