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 subjected to craniectomy alone. dMCAO but not craniectomy caused neurodegeneration and cerebral infarction, but both procedures induced an appreciable increase in BBB permeability to Evans blue dye (EBD), fluorescein, and endogenous albumin but not to 10 kD 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 craniectomy 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.
Significance Statement
Craniectomy is often performed in preclinical stroke studies. In the conventional middle cerebral artery occlusion (MCAO) model involving suture insertion, craniectomy is required to allow laser Doppler flowmetry, which is key for ensuring complete occlusion and minimizing suture-induced brain hemorrhage. In various distal middle cerebral artery occlusion (dMCAO) models, craniectomy is required to enable direct ligation of the cerebral arteries. However, in this study, we found that craniectomy is a major cause of BBB disruption in preclinical stroke models. This has major implications for preclinical data interpretation and translational stroke research, as most previous studies (including ours) were carried out under the wrong assumption that BBB disruption and cerebral edema in these models are caused by ischemia/neuronal injuries per se.
Footnotes
The authors declare no competing financial interests.
This study was supported by research grants from the China Medical University (CMU101-NSC-03-2), the Ministry of Science and Technology (MOST109-2320-B-039-010), the National Health Research Institutes (NHRI-EX111-10803NI) and the ‘Drug Development Center, China Medical University’ from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. CWL and EYW were supported by undergraduate student research awards from the Ministry of Science and Technology (MOST105-2815-C-039-046-B; MOST106-2813-C-039-066-B; MOST108-2813-C-039-125-B to CWL; MOST110-2813-C-039-027-B to EYW) and Long-Term Scholarship for Gifted Students from the Hsing Tian Kung Culture and Education Development Foundation (to EYW).
Che-Wei Liu and Eric Yuhsiang Wang Co-first authors.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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