Spreading depolarization causes reperfusion failure after cerebral ischemia
biorxiv(2022)
摘要
Background Despite successful recanalization to treat acute ischemic stroke, reperfusion failure associated with poor functional outcomes develops in half of the patients. The cause of reperfusion failure remains the subject of intensive research. Here, we explore the possibility that spreading depolarization (SD), a potent ischemic injury mechanism is a significant contributor and reliable predictor of reperfusion failure.
Methods Young adult male and female C57BL/6 mice (n=69) were anesthetized with isoflurane (0.6-0.9%) and prepared for transcranial optical imaging. After 10 min of baseline, incomplete global forebrain ischemia was induced by transient (45 min) bilateral common carotid artery (CCA) occlusion, followed by 75 min reperfusion. SD and cerebral blood flow (CBF) changes were visualized with intrinsic optical signal imaging and laser speckle contrast imaging. To block SD, the irreversible NMDA receptor antagonist MK801 was applied (0.3 mg/kg, i.p., n=29). Neurological deficit was evaluated at baseline and post-ischemia with a composite Garcia Neuroscore scale. Collaterals of the circle of Willis were examined after loading the vasculature with carbon black ink. Ischemic neuronal injury was evaluated in hematoxylin-eosin-stained brain sections.
Results SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1±4.6 vs. 33.6±4.4 %, SD vs. no SD). The failure of later reperfusion (44.4±12.5 %) was invariably linked to previous ischemic SD. In contrast, reperfusion was adequate (98.9±7.4 %) in hemispheres devoid of SD during ischemia. CBF reduced below the perfusion threshold of SD, when the P1 segment was absent in the circle of Willis. SD occurrence and the linked reperfusion failure were associated with poor neurologic function, and greater neuronal necrosis. The inhibition of SD with MK801 significantly improved reperfusion.
Conclusions SD occurrence during ischemia impairs later reperfusion, prognosticating poor functional outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals.
### Competing Interest Statement
The authors have declared no competing interest.
* 2VO
: Bilateral common carotid artery occlusion (“two-vessel occlusion”)
20-HETE
: 20-Hydroxyeicosatetraenoic acid
ACA
: Anterior cerebral artery
AComA
: Anterior communicating artery
BA
: Basilary artery
C. CoW
: Complete circle of Willis
CBF
: Cerebral blood flow
CCA
: Common carotid artery
CoW
: Circle of Willis
GN
: Garcia Neuroscore
HE
: Hematoxylin-eosin
I. CoW
: Incomplete circle of Willis
ICA
: Internal carotid artery
IOS
: Intrinsic optical signal
LASCA
: Laser speckle contrast analysis
MCA
: Middle cerebral artery
NMDA
: N-methyl D-aspartate
PCA
: Posterior cerebral artery
PComA
: Posterior communicating artery
ROI
: Region of interest
SD
: Spreading depolarization
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关键词
Circle of Willis,collaterals,ischemic stroke,reperfusion,spreading depolarization
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