Characterization of a novel model of global forebrain ischaemia–reperfusion injury in mice and comparison with focal ischaemic and haemorrhagic stroke

• Published in: Scientific reports Vol. 10; no. 1; p. 18170
• Main Authors: Lee, Natasha Ting, Selan, Carly, Chia, Joanne S. J., Sturgeon, Sharelle A., Wright, David K., Zamani, Akram, Pereira, Melrine, Nandurkar, Harshal H., Sashindranath, Maithili
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.10.2020; Nature Publishing Group
• Subjects: 692/308/1426; 692/617/375/1370; 692/617/375/534; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Apoptosis - immunology; Blood diseases; Blood flow; Blood-brain barrier; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - pathology; Brain; Brain injury; Carotid arteries; Carotid Arteries - physiopathology; Carotid artery; Cerebral blood flow; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Chemokines; Collagen; Collagenase; Collagenases - administration & dosage; Collagenases - adverse effects; Cytokines; Cytokines - genetics; Cytokines - immunology; Disease Models, Animal; Edema; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Forebrain; Hemorrhage; Hemorrhagic Stroke - drug therapy; Hemorrhagic Stroke - immunology; Hemorrhagic Stroke - pathology; Hemorrhagic Stroke - physiopathology; Humanities and Social Sciences; Humans; Inflammation; Ischemia; Ischemic Stroke - drug therapy; Ischemic Stroke - immunology; Ischemic Stroke - pathology; Ischemic Stroke - physiopathology; Lesions; Ligation; Locomotion - physiology; Magnetic Resonance Imaging; Male; Mice; Middle Cerebral Artery - physiopathology; multidisciplinary; Neostriatum; Oxidative stress; Prosencephalon - blood supply; Prosencephalon - diagnostic imaging; Prosencephalon - drug effects; Prosencephalon - pathology; Protective Agents - therapeutic use; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - immunology; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Science; Science (multidisciplinary); Stroke; Toll-Like Receptors - genetics; Transcription; Transcriptional Activation - immunology; Vascular cell adhesion molecule 1; Veins & arteries
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-75034-4

Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia–reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood–brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.