Abstract
Transient middle cerebral artery occlusion (tMCAO) model is widely used to mimic human focal ischemic stroke in order to study ischemia/reperfusion brain injury in rodents. In tMCAO model, intraluminal suture technique is widely used to achieve ischemia and reperfusion. However, variation of infarct volume in this model often requires large sample size, which hinders the progress of preclinical research. Our previous study demonstrated that infarct volume was related to the success of reperfusion although the reason remained unclear. The aim of present study is to explore the relationship between focal thrombus formation and model reproducibility with respect to infarct volume. We hypothesize that suture-induced thrombosis causes infarct volume variability due to insufficient reperfusion after suture withdrawal. Seventy-two adult male CD-1 mice underwent 90 minutes of tMCAO with or without intraperitoneal administration of heparin. Dynamic synchrotron radiation microangiography (SRA) and laser speckle contrast imaging (LSCI) were performed before and after tMCAO to observe the cerebral vascular morphology and to measure the cerebral blood flow in vivo. Infarct volume and neurological score were examined to evaluate severity of ischemic brain injury. We found that the rate of successful reperfusion was much higher in heparin-treated mice compared to that in heparin-free mice according to the result of SRA and LSCI at 1 and 3 hours after suture withdrawal (p<0.05). Pathological features and SRA revealed that thrombus formed in the internal carotid artery, middle cerebral artery or anterior cerebral artery, which blocked reperfusion following tMCAO. LSCI showed that cortical collateral circulation could be disturbed by thrombi. Our results demonstrated that suture-induced thrombosis was a critical element, which affects the success of reperfusion. Appropriate heparin management provides a useful approach for improving reproducibility of reperfusion model in mice.
Highlights
A reproducible cerebral ischemia/reperfusion model is critical for the development of ischemic therapy in rodent
anterior cerebral artery (ACA), MCA, posterior cerebral artery (PCA), pterygopalatine artery (PPA) and internal carotid artery (ICA) in the mouse brain before transient middle cerebral artery occlusion (tMCAO) with MCA and ACA un-perfused after MCAO (Figure 2A)
Several modelinherent complications still exist: 1) filament insertion could result in inadequate MCAO, which was related to the shape and diameter of the suture [7,8]; 2) SAH could occur and complicate the pathophysiological relevance of the model [8,9]; 3) high mortality and infarct volume variability could occur in relation to the high variation of posterior communicating arteries (PcomAs) [10,11]; and 4) hyperthermia during and post ischemia could complicate the interpretations of results [12,27]
Summary
A reproducible cerebral ischemia/reperfusion model is critical for the development of ischemic therapy in rodent. It is important to develop a reproducible cerebral ischemia/reperfusion model in rodent for better studying the mechanisms of ischemic stroke and developing feasible therapies. Post-ischemic reperfusion occurs frequently in human ischemic stroke when occlusion was caused by embolism. To mimic this clinical situation, intraluminal suture transient middle cerebral artery occlusion (tMCAO) model was developed in rats and mice [5,6]. This tMCAO model, being widely accepted for reperfusion study, allows reperfusion after suture withdrawal
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