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Secondary Brain Damage in Mouse Models of Focal and Global Ischaemia and Haemorrhagic Stroke: A Comparative Study

1Monash University, Australian Centre for Blood Diseases, Central Clinical School, Melbourne, Australia, 2Monash University, Dept of Neuroscience, Central Clinical School, Melbourne, Australia, 3Alfred Health, Clinial Haematology, Melbourne, Australia

Abstract Number: PB0099

Meeting: ISTH 2020 Congress

Theme: Arterial Thromboembolism » Cerebrovascular Disorders

Background: Stroke is caused due to obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (intracerebral haemorrhage; ICH). Global brain ischaemia occurs when cerebral blood flow is restricted e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia-reperfusion (I/R) injury which further worsens outcome.

Aims: To study secondary injury mechanisms in global and focal ischaemia and to compare it with ICH using standardised readouts for inflammation, endothelial dysfunction, blood-brain barrier (BBB) damage and apoptosis.

Methods: We compared the conventionally used model of I/R injury (middle cerebral artery occlusion; MCAo) with ICH (collagenase model) and a newly developed model of global I/R injury (dual carotid artery ligation; DCAL).

Results: MRI revealed that DCAL produced smaller bilateral striatal lesions, whereas MCAo produced a larger focal corticostriatal lesion. Striatal lesion volume was relatively smaller after ICH. After global ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed that MCAo and ICH had significantly worsened mobility. BBB breakdown was seen in both hemispheres of the brain after DCAL whereas apoptotic activity was highest in the haemorrhage model. VCAM-1 upregulation was specific to ischaemia, but increased complement receptor (C5aR) mRNA was detected in all three conditions. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines was seen in the three models.

Conclusions: Given the lack of success in addressing neuroprotection in stroke, laboratory studies comparing more than one ischaemic stroke model or ischaemic and haemorrhagic stroke models are important, but uncommon. The establishment of multiple readouts for different pathophysiological processes can help pinpoint drugs that might be effective under conditions of both ischaemic and haemorrhagic stroke, thereby also eliminating requirement for sophisticated neuroimaging prior to administration. This work also offers strategies to identify drugs that might cause haemorrhagic transformation when developed for treatment of ischaemic stroke.

To cite this abstract in AMA style:

Lee N, Selan C, Chia J, Sturgeon S, Wright D, Zamani A, Pereira M, Nandurkar H, Sashindranath M. Secondary Brain Damage in Mouse Models of Focal and Global Ischaemia and Haemorrhagic Stroke: A Comparative Study [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/secondary-brain-damage-in-mouse-models-of-focal-and-global-ischaemia-and-haemorrhagic-stroke-a-comparative-study/. Accessed October 2, 2023.

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