title: Systemic inflammation affects reperfusion following transient cerebral ischaemia.
abstract: Reperfusion after stroke is critical for improved patient survival and recovery and can be achieved clinically through pharmacological (recombinant tissue plasminogen activator) or physical (endovascular intervention) means. Yet these approaches remain confined to a small percentage of stroke patients, often with incomplete reperfusion, and therefore there is an urgent need to learn more about the mechanisms underlying the no-reflow phenomenon that prevents restoration of adequate microvascular perfusion. Recent evidence suggests systemic inflammation as an important contributor to no-reflow and to further investigate this here we inject interleukin 1 (IL-1) i.p. 30 min prior to an ischaemic challenge using a remote filament to occlude the middle cerebral artery (MCA) in mice. Before, during and after the injection of IL-1 and occlusion we use two-dimensional optical imaging spectroscopy to record the spatial and temporal dynamics of oxyhaemoglobin concentration in the cortical areas supplied by the MCA. Our results reveal that systemic inflammation significantly reduces oxyhaemoglobin reperfusion as early as 3h after filament removal compared to vehicle injected animals. CD41 immunohistochemistry shows a significant increase of hyper-coagulated platelets within the microvessels in the stroked cortex of the IL-1 group compared to vehicle. We also observed an increase of pathophysiological biomarkers of ischaemic damage including elevated microglial activation co-localized with interleukin 1α (IL-1α), increased blood brain barrier breakdown as shown by IgG infiltration and increased pyknotic morphological changes of cresyl violet stained neurons. These data confirm systemic inflammation as an underlying cause of no-reflow in the post-ischaemic brain and that appropriate anti-inflammatory approaches could be beneficial in treating ischaemic stroke.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK.
authors.forename: F
authors.initials: F
authors.lastname: Burrows
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Haley
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Scott
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Coutts
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK.
authors.forename: C B
authors.initials: CB
authors.lastname: Lawrence
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester, UK. Electronic address: i.schiessl@manchester.ac.uk.
authors.forename: I
authors.initials: I
authors.lastname: Schiessl
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000473:pathology; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D010108:Oxyhemoglobins / Q000378:metabolism; D015424:Reperfusion; D013057:Spectrum Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology*; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D007375:Interleukin-1; D008840:Microfilament Proteins; D010108:Oxyhemoglobins
keywords: Co-morbidity; Interleukin-1; Interleukin-1β; Middle cerebral artery occlusion; Optical imaging; Reperfusion; Spectroscopy; Stroke; Systemic inflammation