|Year : 2022 | Volume
| Issue : 2 | Page : 33-39
Reperfusion and reperfusion injury after ischemic stroke
Jie Gao1, Alexandra Wehbe2, Fengwu Li3, Naveed Chaudhry4, Changya Peng5, Xiaokun Geng6, Yuchuan Ding5
1 Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China
2 Department of Health and Social Behavior, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
3 Department of Neurology, China-America Institute of Neuroscience, Luhe Hospital, Capital Medical University, Beijing, China
4 Lake Erie College of Osteopathic Medicine at Seton Hill, Greensburg, Pennsylvania, USA
5 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
6 Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA; Department of Neurology, China-America Institute of Neuroscience, Luhe Hospital, Capital Medical University, Beijing, China
|Date of Submission||20-May-2022|
|Date of Acceptance||09-Jun-2022|
|Date of Web Publication||30-Jun-2022|
Department of Neurology, Beijing Luhe Hospital, Capital Medical University, No. 82 Xinhua South Road, Tongzhou District, Beijing 101149
Source of Support: None, Conflict of Interest: None
Objectives: Stroke is a leading cause of distress, disability, and death worldwide. The goal of reperfusion therapy for acute ischemic stroke (AIS) is the restoration of cerebral blood flow (CBF). If initiated too late, however, reperfusion therapy may paradoxically exacerbate tissue injury. Beyond a critical period, restoration of CBF may amplify already deranged inflammatory, apoptotic, and metabolic processes, increasing neurologic damage. This study was conducted to evaluate how timing of reperfusion therapy affects inflammatory, apoptotic, and metabolic responses after AIS.
Materials and Methods: A total of 49 male Sprague-–Dawley rats were divided into four groups, either subject to 2- or 4-h of middle cerebral artery occlusion (MCAO) before reperfusion, 24 h of MCAO with no reperfusion, or a control group. Seven rats from each group were used for histological assay and for Western Blotting, respectively.
Results: Infarction volumes were slightly decreased in the 2- and 4-h ischemia groups compared to the permanent ischemia group (49.5%, 49.3%, and 53.1%, respectively). No significant variation in neurological deficit scores was observed when comparing 2- and 4-h ischemia groups to the permanent ischemia group. Glucose metabolism protein (GLUT1 and GLUT3) expression was increased in all ischemia groups compared to the control group (P < 0.05). Expression of pro-inflammatory proteins (tumor necrosis factor α, interleukin-1 β, intercellular adhesion molecule-1, and vascular cell adhesion protein-1 was significantly increased in all ischemia groups compared to the control group at 24 (P < 0.05). There was significantly increased expression of pro-apoptotic proteins (caspase-3, cleaved caspase-3, and Bax) and significantly reduced anti-apoptotic protein (Bcl-2) expression in all the ischemia groups compared to the control group at 24 h (P < 0.05). Nuclear factor kappa (NF-κB) expression was significantly increased in all ischemia groups compared to the control group at 24 h (P < 0.05).
Conclusion: The results of this study displayed relationships between the timing of reperfusion therapy and the multiple pathways discussed. There is potential utility in exploring and targeting components of the post-AIS inflammatory, apoptotic, and metabolic responses for neuroprotection against AIS and reperfusion injury.
Keywords: Acute ischemic stroke, apoptosis, inflammation, middle cerebral artery occlusion, nuclear factor kappa expression
|How to cite this article:|
Gao J, Wehbe A, Li F, Chaudhry N, Peng C, Geng X, Ding Y. Reperfusion and reperfusion injury after ischemic stroke. Environ Dis 2022;7:33-9
| Introduction|| |
Acute ischemic stroke (AIS) accounts for approximately 62% of strokes globally. Reperfusion therapy, the mainstay treatment for AIS, aims to restore cerebral blood flow (CBF). However, the therapeutic window for reperfusion is narrow. Intervention beyond this critical period can precipitate paradoxical neurologic damage and subsequent hemorrhagic transformation, a debilitating complication known as reperfusion injury., Reperfusion injury is a devastating complication that worsens patient outcomes and can sometimes be fatal. AIS may cause neuronal tissue injury due to the loss of blood supply, nutrients, and oxygen. Transport of metabolic waste is also hindered and the fragile brain tissue experiences cerebral ischemia which incites disturbances in inflammatory, apoptotic, and metabolic pathways. Abrupt CBF restoration into ischemic tissue may overload the already deranged systems and depleted antioxidants, resulting in cerebral edema and cell extravasation. Subsequent generation and leakage of reactive oxygen species (ROS) can activate inflammatory and apoptotic pathways, which further augments ROS production. This results in the vicious cycle of neurological damage underlying reperfusion injury.,, There is also evidence that derangements in glucose metabolism are implicated in the underlying mechanisms of ischemic and reperfusion injury.
Cerebral ischemia induces changes in glucose metabolism through facilitative diffusion glucose transporters (GLUTs). GLUT1 and GLUT3 are the main glucose transporters in the brain. GLUT1 is expressed in astrocytes and endothelial cells of the blood–brain barrier, while GLUT3 is a neuronal transporter., When cerebral oxygen is reduced, GLUT1 and GLUT3 are upregulated as a compensatory response to metabolic deficit to prevent cellular damage. However, this may cause excessive cerebral glycolysis, resulting in ROS production, contributing to neurologic damage in ischemic and reperfusion injury.
Cerebral ischemia also induces the expression of pro-inflammatory molecules such as intercellular adhesion molecule (ICAM-1), vascular cell adhesion protein (VCAM-1), tumor necrosis factor α (TNF-α), and interleukin-1 (IL-1) β. ICAM-1 and VCAM-1. These molecules are known as cell adhesion molecules (CAMs) and they recruit leukocytes to ischemic tissue immediately poststroke, facilitating inflammation and worsening ischemic injury., IL-1 β is a pro-inflammatory cytokine shown to contribute to acute inflammation through initiating astrogliosis and releasing toxic substances such as chemokines and CAMs., TNF-α is another inflammatory cytokine shown to have both neurotoxic and neuroprotective effects.,,
AIS also induces pro-apoptotic molecular cascades. Caspase-3, cleaved caspase-3, and Bax are pro-apoptotic proteins that contribute to neurologic damage by facilitating neuronal cell apoptosis. Bcl-2 is an anti-apoptotic protein that can block apoptosis and necrosis, serving as a metric for neuroprotection., NF-κB is a transcription factor that upregulates the expression of pro-inflammatory and pro-apoptotic genes, shown in ischemia models to contribute to neurologic tissue damage.
In this study, we aimed to investigate the effect of time of reperfusion on neurologic damage post-AIS by looking at inflammatory, metabolic, and apoptotic responses postreperfusion.
| Materials and Methods|| |
Forty-nine adult male Sprague-Dawley rats (280–300 g, Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) were used in this study. The protocol, in accordance with the NIH Guide for the Care and Use of Laboratory Animals, was approved by the Animal Care and Use Committee of Capital Medical University. Animals were randomly divided into four groups: one sham ischemia group (control, n = 7) and three ischemia groups, respectively, subjected to 2 h of ischemia before reperfusion (2 h IS/24 h RE, n = 14), 4 h of ischemia before reperfusion (4 h IS/24 h RE, n = 14), and 24 h of ischemia with no reperfusion (24 h IS, n = 14). Seven rats from each group were used for histological assay and for Western blotting, respectively. Animals were sacrificed 24 h later and rats from the sham group were sacrificed at corresponding time points for comparison.
Focal cerebral ischemia and reperfusion
Ischemic rats were subjected to 2, 4, or 24 h of right middle cerebral artery occlusion (MCAO). Rats were anesthetized in a chamber using 3% isoflurane and a mixture of 70% nitrous oxide and 30% oxygen. The rats were then transferred to a surgical table where anesthesia was maintained with a facemask that delivered 1% isoflurane from a calibrated precision vaporizer. Poly-L-lysine-coated nylon (4.0) sutures were used to generate infarcts with minimal inter-animal variability. During the unilateral MCAO procedure, CBF was monitored continuously using the laser speckle technique and rectal temperature using a heating pad. Rectal temperatures were maintained between 36.5°C and 37.5°C. Ipsilateral ischemic hemispheres were used for further molecular analysis.
Cerebral infarct volume
Twenty-four hours following reperfusion (and at equivalent time points in permanent ischemia rats), the rats' brains were dissected, cut into 2-mm thick slices with a brain matrix, and treated with (2, 3, 5-triphenyltetrazolium chloride, Sigma, USA) for staining. A previously validated indirect method for calculating infarct volume was used to minimize error caused by edema.
Previously validated modified 5-point and 12-point scoring systems, proposed by Zea Longa (5-point scoring system) and Belayev et al. (12-point scoring system), were used to examine the severity of neurological deficits and used to confirm brain injury. The MCAO was considered unsuccessful if scores were <1. 10% of rats in our study scored <1 and were subsequently excluded from the analysis. Exclusion from the study was further confirmed by an autopsy demonstrating a lack of core infarction.
Rats were sacrificed 24 h following reperfusion (and at equivalent time points in permanent ischemia rats) and Western blot analysis was used to examine protein expression. Samples were incubated with a primary antibody including GLUT1, GLUT3, caspase-3, cleaved caspase-3, Bax, Bcl-2, IL-1 β, ICAM-1, VCAM-1, TNF-α, NF-κB (1:1000, CST, Boston, MA, USA) for 24 h at 4°C. The samples were further incubated with a goat anti-rabbit IgG-HRP secondary antibody (1:1000, Santa Cruz, Dallas, TX, USA) for all primary antibodies. Western blot images for molecules were analyzed using an image analysis program (Image J 1.42, National Institutes of Health, Bethesda, MD, USA) to quantify protein expressions according to relative image density. The calculations of Western blotting images were normalized according to their corresponding β-actin.
Statistical analyses were performed with SPSS Statistics for Windows, Version 17.0 (SPSS Inc., Chicago, IL, USA). Differences among groups were assessed using one-way ANOVA with a statistical significance level of P < 0.05. Post hoc comparison among groups was performed using the least significant difference method.
| Results|| |
Brain infarction and neurological defects
Infarct volumes observed in the permanent ischemia groups were 53.1% at 24 h [Figure 1]a and [Figure 1]b. Infarction volumes were slightly decreased to in the 2-h and 4-h reperfusion groups (49.5% and 49.3%, respectively). Neurological deficits detected by the 5-and 12-point [Figure 1]c and [Figure 1]d scoring systems were 3.0 or 7.1 points at 24 h in the permanent ischemia group. No statistically significant variation was observed in the 2-h (3.5 and 8.3 points) and 4-h (3.0 and 6.0 points) ischemia groups compared to the permanent ischemia group.
|Figure 1: Brain infarct and neurological deficits. (a) TTC images of brain infarct after ischemia with or without reperfusion at 24 h. (b) Quantification of the TTC images showed increasing infarct volumes. Compared to the permanent ischemia group, the 2-h and 4-h ischemia groups had slightly decreased infarct volumes. There were no significant variations in neurological deficits measured by the 5-point (c) and 12-point (d) scoring systems in these ischemia groups. TTC: triphenyltetrazolium chloride|
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Glucose metabolism protein expression
Glucose metabolism protein (GLUT1 and GLUT3) expression was increased in all ischemia groups compared to the control group [*P < 0.05, [Figure 2]]. GLUT protein expression was increased in the 2-h ischemia group compared to the permanent ischemia group, while the 4-h ischemia group had reduced levels of GLUT expression compared to the permanent ischemia group. The 2-h ischemia group had higher levels of GLUT1 [##P < 0.01, [Figure 2]a] and GLUT3 compared to the 4-h ischemia group, although GLUT3 did not reach a significant level [Figure 2]b.
|Figure 2: Glucose metabolism expression. Alterations in (a) GLUT1 and (b) GLUT3 protein expression after ischemia were found. Compared to the control group, all the ischemia groups demonstrated increased GLUT1 and GLUT3 expression (*P < 0.05, A and B). The 2-h ischemia group had slightly increased expression of both GLUT1 and GLUT3 protein while the 4-h ischemia group had reduced levels of GLUT1 and GLUT3 compared to the permanent ischemia group (A and B). The 2-h ischemia group had higher levels of GLUT1 (##P < 0.01, A) and GLUT3 (b) expression compared to the 4-h ischemia group. GLUT1: Glucose metabolism protein|
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Inflammatory protein expression
Expression of pro-inflammatory proteins (TNF-α, IL-1 β, ICAM-1, and VCAM-1) was significantly increased in all ischemia groups compared to the control group at 24 h with or without reperfusion [*P < 0.05, [Figure 3]]. The 2-h ischemia group had significantly decreased levels of ICAM-1 [##P < 0.01, [Figure 3]c] and VCAM-1 [###P < 0.001, [Figure 3]d], while having increased levels of TNF-α [###P < 0.001, [Figure 3]a] and of IL-1 β [not statistically significant, [Figure 3]b] compared to the permanent ischemia group. Compared to the 4-h ischemia group, the 2-h ischemia group demonstrated significantly reduced expression of ICAM-1 [###P < 0.001, [Figure 3]c] and VCAM-1 [##P < 0.01, [Figure 3]d] and increased expression of TNF-α [###P < 0.001, [Figure 3]a] IL-1 β [not statistically significant, [Figure 3]b]. In addition, the 4-h ischemia group had slightly reduced VCAM-1 and TNF-α protein expression and increased IL-1 β and ICAM-1 protein expression compared to the permanent ischemia group, however, these changes were not statistically significant [Figure 3].
|Figure 3: Inflammatory protein expression. Alterations in (a) TNF-α, (b) IL-1 β, (c) ICAM-1, and (d) VCAM-1 expression after ischemia were demonstrated. Compared to the control group, all of the ischemia groups saw an increased expression of inflammatory proteins (*P < 0.05, a-d) at 24 h. The 2-h ischemia group had significantly reduced expression of ICAM-1 (##P < 0.01, c) and VCAM-1 (###P < 0.001, d), and increased IL-1 β (#P < 0.05, b) and TNF-α (###P < 0.001, a) levels compared to the permanent ischemia group. The same trend was also found when compared to the 4-h ischemia group (#P < 0.05, a-d). The 4-h ischemia group had slightly reduced levels of VCAM-1, and increased IL-1 β, TNF-α, and ICAM-1 levels compared to the permanent ischemia group (a-d). TNF-α: Tumour necrosis factor α, IL-1: Interleukin-1, ICAM-1: Intercellular adhesion molecule, VCAM-1: Vascular cell adhesion protein|
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Pro- and anti-apoptotic protein expression
There was significantly increased expression of pro-apoptotic proteins (caspase-3, cleaved caspase-3 and Bax) and significantly reduced anti-apoptotic protein (Bcl-2) expression observed in all the ischemia groups compared to the control group at 24 h with or without reperfusion [*P < 0.05, [Figure 4]]. Both the 2-h and 4-h ischemia groups had slightly increased caspase-3 expression and slightly reduced Bax expression compared to the permanent ischemia group [Figure 4]a and [Figure 4]c. Levels of cleaved caspase-3 expression were slightly reduced in the 2-h ischemia group, while levels of cleaved caspase-3 were increased in the 4-h ischemia group compared to the permanent ischemia group [Figure 4]b. Both the 2-h and 4-h ischemia groups demonstrated the same level of Bcl-2 expression when compared to the permanent ischemia group [Figure 4]d. Furthermore, the Bcl-2/Bax ratio, a measure of the interplay between Bax and Bcl-2, was significantly increased in all three ischemia groups when compared to the control group [***P < 0.001, [Figure 4]e. There was no significant variation in the Bcl/Bax ratio among the ischemia groups [Figure 4].
|Figure 4: Pro- and Anti-apoptotic Protein Expression. Alterations in levels of (a) caspase-3, (b) cleaved caspase-3, (c) Bax and (d) Bcl-2 protein as well as in the (e) Bcl-2/Bax ratio after ischemia were demonstrated. Compared to control group, all the ischemia groups saw an increase in the expression of pro-apoptotic proteins (*P < 0.05, a-c), reduced levels anti-apoptotic proteins (*P < 0.05, d), and increases in the Bcl-2/Bax ratio (***P < 0.001, e) at 24 h. Both the 2-h and 4- ischemia groups had slightly increased caspase-3 expression (a) and reduced Bax expression (c) compared to the permanent ischemia group. The 2-h ischemia group had slightly reduced cleaved caspase-3 level, while an increase was observed in 4-h ischemia group compared to the permanent ischemia group (b). Both the 2-hour and 4-h ischemia groups saw the same levels of Bcl-2 (d) and Bcl-2/Bax ratio (e) compared to the permanent ischemia group|
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Nuclear factor kappa protein expression
NF-κB expression was significantly increased in all the ischemia groups compared to the control groups at 24 h with or without reperfusion [*P < 0.05, [Figure 5]]. The 2-h ischemia group demonstrated slightly increased NF-κB protein expression, while the 4-h ischemia group had slightly reduced levels of NF-κB compared to the permanent ischemia group. The 2-h ischemia group had significantly increased NF-κB levels compared to 4-h ischemia group [#P < 0.05, [Figure 5]].
|Figure 5: NF-κB Expression. Altered levels of NF-κB expression after ischemia were demonstrated. Compared to the control group, all the ischemia groups saw an increased expression of inflammatory proteins (*P < 0.05) at 24 h. The 2-h ischemia group had slightly increased NF-κB protein expression while the 4-h ischemia group had slightly reduced NF-κB levels compared to the permanent ischemia group. The 2-h ischemia group had significantly increased NF-κB levels compared to the 4-h ischemia group (#P < 0.05). NF-κB: Nuclear factor-kappa|
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| Discussion|| |
We found no statistically significant reduction in neurologic infarct volumes and deficits when reperfusion therapy was initiated 2- or 4-h poststroke compared to the groups that received no reperfusion therapy. This indicates that initiating reperfusion therapy after a critical time point may not benefit patients post-AIS, while still exposing them to the risk of increased neurologic insult from reperfusion injury.
We also found that GLUT1 and GLUT3 expression was increased in all ischemic groups compared to the control group. These findings reaffirm previous work which has asserted that cerebral GLUT expression is upregulated in response to ischemic brain damage. This phenomenon may be attributed to the increased energy demand and utilization of glucose by neurons under stress.,, We also found that when comparing the 2- and 4-h reperfusion groups to the permanent ischemia group, the 2-h ischemia group had significantly increased expression of both GLUT1 and GLUT3, whereas the 4-h ischemia group had lower levels of GLUT1 and GLUT3 expression. These findings may imply that the effects of reperfusion therapy on cerebral glucose metabolism are dynamic in nature and are influenced by the time at which reperfusion therapy is initiated. These findings also may indicate that dysfunctional cerebral glucose metabolism may contribute to ischemic and reperfusion injury.
These findings contribute to the growing body of literature which suggests that changes in glucose metabolism could have beneficial or deleterious effects on poststroke ischemic brain tissue. Studies have shown that upregulating glucose metabolism can enhance glucose delivery and preserve ATP levels in ischemic tissue., The role of glucose in the production of ROS provides another mechanism by which derangements in glucose metabolism may play a role in reperfusion.,, The formation of ROS requires oxygen and thus cannot occur in the context of anaerobic conditions in severe ischemia. Reperfusion therapy creates an influx of oxygen, which could facilitate ROS production and subsequently increase neurologic tissue damage.
Our study also demonstrated that pro-inflammatory molecules were significantly increased in all ischemic groups compared to the control group. This supports existing literature that cerebral ischemia promotes an aberrant immune response involving pro-inflammatory molecules such as IL-1 β and TNF-α as well as CAMs such as ICAM-1 and VCAM-1.,, In association with the increased levels of IL-1 β and TNF-α compared to the permanent ischemia group, the levels of CAMs were significantly upregulated in the 2 h ischemia group. These results suggest the inflammatory reaction demonstrated by the expression of different inflammatory factors during different reperfusion times caused ischemic and reperfusion injury. These findings may be utilized to inform and benefit future studies that assess targeting these inflammatory pathways to increase neuroprotection post-AIS.
Increased levels of pro-apoptotic proteins, the Bcl-2/Bax ratio, and reduced levels of anti-apoptotic proteins were found among all ischemia groups when compared to the control group. These findings support existing evidence that post-AIS with or without reperfusion is associated with increased levels of neuronal cell apoptosis., Once again, these results suggested that early reperfusion is necessary to prevent induced ischemia and reperfusion injury by inducing pro- and decreasing anti-apoptotic protein expression.
NF-κB expression was significantly increased in all ischemia groups compared to the controls. This supports existing evidence that NF-κB is an upstream regulator of apoptosis and inflammation poststroke.,, The 2-h ischemia group showed significantly increased levels of NF-κB compared to the 4-h ischemia group. These findings indicate that NF-κB may be an upstream molecule regulating brain injury after ischemic stroke. The utility of NF-κB as a therapeutic target is a recent avenue of investigation that thus far has conflicting results. Some studies showed that inhibition of NF-κB had a neuroprotective benefit post-AIS, whereas others found adverse effects that worsened AIS outcomes.,,
A plethora of studies have demonstrated the tight relationship of ischemic and reperfusion injury with glucose metabolism, inflammatory reactions, and apoptotic molecules. During the beginning period of a stroke, blood glucose levels are increased, possibly due to preexisting diabetes or an elevated cortisol and norepinephrine state from the stress response. A hyperglycemic state shunts glycolysis toward anaerobic metabolism causing lactic acidosis. These shunts add to the abundant levels of ROS and NF-kB pathway signaling that are already present from other pathways triggered by hypoperfusion.
Additional mechanisms that elevate ROS in ischemic and reperfusion injuries are the induction of xanthine oxidase, NADPH oxidase, and NOS. Ultimately, these pathways converge into inflammation by activation of immune cells and cytokine build up. Concurrently, there is a significant release of apoptotic molecules when injury is prolonged. Hypoxia initiates the intrinsic pathway of apoptosis; a downstream of pro-apoptotic proteins are expressed, like caspase 3, to finalize the process of apoptosis.
Ischemic and reperfusion injury are caused by a myriad of complex molecular interactions in metabolic, inflammatory, and apoptotic dysfunction. Our study demonstrates the clear connection between these three molecular pathways and post-AIS ischemic injury which sets the precedent for these pathways to be augmented by reperfusion therapy. Molecules in these pathways may serve as targets for therapeutic intervention to prevent further neurologic damage by way of reperfusion injury.
| Conclusion and Perspectives|| |
Our study has reaffirmed existing evidence that metabolic, inflammatory, and pro-apoptotic processes are implicated in AIS and reperfusion injury. These processes can contribute to neurologic damage, worsening outcomes post-AIS. Our study has also found that the relationship between time to reperfusion and these pathophysiologic pathways is dynamic in nature. Various studies have been conducted to investigate the role of anti-inflammatory, anti-apoptotic, and glucose-regulating therapies targeting these pathways in AIS and have shown conflicting results. Future clinical and laboratory studies should evaluate these therapeutic targets and how time to reperfusion influences their neuroprotective potential. Therapies targeting these pathways may work synergistically with reperfusion therapy to safely extend the window for reperfusion therapy, reduce complications, and improve neurologic outcomes.
Financial support and sponsorship
This work was partially supported by the Merit Review Award (I01RX-001964-01), the Beijing Natural Science Foundation (7214239), and the Laboratory Development Funds of Luhe Hospital (2022).
Conflicts of interest
Dr. Yuchuan Ding is an Editor-in-Chief, Dr. Xiaokun Geng is an Editorial Board member of Environmental Disease. The article was subject to the journal's standard procedures, with peer review handled independently of them and their research groups.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]