Early Reperfusion Following Ischemic Stroke Provides Beneficial Effects, Even After Lethal Ischemia with Mature Neural Cell Death

Abstract

Ischemic stroke is a critical disease caused by cerebral artery occlusion in the central nervous system (CNS). Recent therapeutic advances, such as neuroendovascular intervention and thrombolytic therapy, have allowed recanalization of occluded brain arteries in an increasing number of stroke patients. Although previous studies have focused on rescuing neural cells that still survive despite decreased blood flow, expanding the therapeutic time window may allow more patients to undergo reperfusion in the near future, even after lethal ischemia, which is characterized by death of mature neural cells, such as neurons and glia. However, it remains unclear whether early reperfusion following lethal ischemia results in positive outcomes. The present study used two ischemic mouse models—90-min transient middle cerebral artery occlusion (t-MCAO) paired with reperfusion to induce lethal ischemia and permanent middle cerebral artery occlusion (p-MCAO)—to investigate the effect of early reperfusion up to 8 w following MCAO. Although early reperfusion following 90-min t-MCAO did not rescue mature neural cells, it preserved the vascular cells within the ischemic areas at 1 d following 90-min t-MCAO compared to that following p-MCAO. In addition, early reperfusion facilitated the healing processes, including not only vascular but also neural repair, during acute and chronic periods and improved recovery. Furthermore, compared with p-MCAO, early reperfusion after t-MCAO prevented behavioral symptoms of neurological deficits without increasing negative complications, including hemorrhagic transformation and mortality. These results indicate that early reperfusion provides beneficial effects presumably via cytoprotective and regenerative mechanisms in the CNS, suggesting that it may be useful for stroke patients that experienced lethal ischemia.

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…Of interest, consistent with a previous study [ 16 ], we found that larger numbers of neutrophils were present within ischemic areas after permanent ischemia compared with those of reperfusion after ischemia [ 25 ]. It has been documented that anoxia/reperfusion injuries promote the adherence of neutrophils to endothelial cells in vitro and that several cell adhesion molecules (e.g., intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin) play an important role in neutrophil migration into endothelial cells [ 31 , 36 , 37 ].…”

“…Recently, Tachibana et al demonstrated that reperfusion following lethal ischemia had beneficial effects such as neurological functional recovery in a mouse model of stroke [ 16 ]. More recently, with the use of a highly reproducible mouse model of middle cerebral artery occlusion (MCAO) [ 14 , 29 , 30 ], we investigated whether reperfusion during stage II can have beneficial effects at acute (1–7 days after MCAO) and chronic (more than 3 weeks after MCAO) periods by focusing on histology and brain function [ 25 ].…”

“…These findings were not different between reperfusion after ischemia with a duration of 90 min and permanent ischemia at post-stroke days 1 and 3. However, compared with permanent ischemia, reperfusion after ischemia with a duration of 90 min reduced BBB permeability at post-stroke day 7 [ 25 ]. Consistent with this observation, a previous study showed that early reperfusion improved BBB permeability, as assessed by T2* perfusion-weighted source images, in patients with stroke during acute periods [ 35 ].…”

“…Consistent with this observation, a previous study showed that early reperfusion improved BBB permeability, as assessed by T2* perfusion-weighted source images, in patients with stroke during acute periods [ 35 ]. Although the mechanism remains unclear, we found that, in comparison with permanent ischemia, reperfusion after ischemia with a duration of 90 min significantly preserved endothelial cells within ischemic areas at post-stroke days 1 and 7 [ 25 ]. In addition, mild BBB disruption in patients with stroke was reversible by early reperfusion [ 35 ].…”

“…Thus, although reperfusion therapies after stroke have focused on rescuing neural cells, vascular lineage cells may represent novel targets of these treatment options. In this review, we introduce our comments based on recent studies performed after early reperfusion under lethal ischemia in a mouse model of stroke [ 16 , 25 ].…”