Optimized mouse model of embolic MCAO: From cerebral blood flow to neurological outcomes.

Abstract

The embolic middle cerebral artery occlusion (eMCAO) model mimics ischemic stroke due to large vessel occlusion in humans and is amenable to thrombolytic therapy with rtPA. However, two major obstacles, the difficulty of the eMCAO surgery and unpredictable occurrence of clot autolysis, had impeded its application in mice. In this study, we modified catheters to produce suitable fibrin-rich embolus and optimized the eMCAO model using cerebral blood flow (CBF) monitored by both laser Doppler flowmetry (LDF) and 2D laser speckle contrast imaging (LSCI) to confirm occlusion of MCA. The results showed that longer embolus resulted in higher mortality. There was a compensatory increase in MCA territory perfusion after eMCAO associated with decreased infarct volume; however, this was only partly dependent on recanalization as clot autolysis was only observed in ∼30% of mice. Cortical CBF monitoring with LSCI showed that the size of peri-core area at 3 h displayed the best correlation with infarct volume that is attributed to compensatory collateral blood flow. The peri-core area best predicted functional outcome after eMCAO. In summary, we developed a reliable eMCAO mouse model that better mimics embolic ischemic stroke in humans, which will increase the potential for successful translation of stroke neuroprotective therapies.