Blood–Brain Barrier Disruption in Preclinical Mouse Models of Stroke Can Be an Experimental Artifact Caused by Craniectomy

Abstract

The pathophysiological features of ischemia-related blood–brain barrier (BBB) disruption are widely studied using preclinical stroke models. However, in many of these models, craniectomy is required to confirm arterial occlusion via laser Doppler flowmetry or to enable direct ligation of the cerebral artery. In the present study, mice were used to construct a distal middle cerebral artery occlusion (dMCAO) model, a preclinical stroke model that requires craniectomy to enable direct ligation of the cerebral artery, or were subjected to craniec-tomy alone. dMCAO but not craniectomy caused neurodegeneration and cerebral infarction, but both proce-dures induced an appreciable increase in BBB permeability to Evans blue dye, fluorescein, and endogenous albumin but not to 10 kDa dextran-FITC, leading to cerebral edema. Using rats, we further showed that BBB disruption induced by craniectomy with no evidence of dural tearing was comparable to that induced by crani-ectomy involving tearing of the dura. In conclusion, our data demonstrated that craniectomy can be a major contributor to BBB disruption and cerebral edema in preclinical stroke models. The implications of this experimental artifact for translational stroke research and preclinical data interpretation are discussed.