Shen-qiang Yan from the Second Affiliated Hospital of Zhejiang University presented their recent studies on posterior circulation stroke. This may indicate that the main cause of SAP is not the exogenous pathogens, but "the Trojan horse," the immune response within the brain (Chapter 9).
The Cerebral Venous System and Stroke
It is very striking what role endothelial cells play in this course and the subsequent bleeding. In addition to further improving the specific imaging technique for cerebral venous evaluation, we are able to collect more information and thus discover more hidden treasures in this field.
Contents
About the Editors
Yan Qu is a professor and director of the Department of Neurosurgery, Tangdu Hospital of Air Force Medical University, Xi'an, Shaanxi, China. Zhongsong Shi is a professor and deputy director of the Department of Neurosurgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Gelatinase- Mediated Impairment of Microvascular Beds in Cerebral
Finally, we documented the available approaches that show protective functions by blocking the vicious circle of gelatinase activation, which may be promising in combined treatment with tPA in AIS. Keywords Gelatinases · Microvascular beds · Cerebral ischemia and reperfusion injury · Extracellular matrix · Mechanism-based inhibitor · tPA.
1 Introduction
In this chapter, we review the role of gelatinases in the proteolytic modulation of microvascular beds within the neurovascular unit (NVU), a conceptual functional structure in the central nervous system (CNS) of neurons, glial cells, endothelial cells, and pericytes along with closely related components of ECM [27, 28]. Understanding how aberrant activity of gelatinases contributing to perturbations of cellular matrix homeostasis occurs in microvascular beds associated with cerebral ischemia and reperfusion injury (CIRI) may hold significant promise for recanalization outcome in ischemic stroke.
2 Microvascular Beds and the Extracellular Matrix (ECM)
The major protein components of the ECM in the CNS include: structural elements (type IV collagens and elastin), specialized proteins (laminins, entactin/nidogen, fibronectin, and vitronectin), and proteoglycans [heparan sulfate proteoglycans (HSPG), perlecan, and agrin] [ 42–49]. Cerebral ischemia is also associated with a decrease in the laminin-binding proteins α6β4 and dystroglycan, and this coincides with astrocyte swelling.
3 Gelatinases Mediate Impairment of Microvascular Beds in CIRI
Detachment of pericytes from the basal lamina and migration of pericytes towards the hypoperfusion lesion may be associated with the expression of pericyte MMPs [81]. Integrin-matrix interactions in the cerebral vasculature may explain the mechanism by which laminin degradation in the ECM mediates endothelial cell loss after ischemia Disruption of ECM gelatin may lead to pericyte shrinkage and loss of pericyte-endothelial interaction.
4 Activation of Gelatinases and Extravasation of tPA into Brain Parenchyma in CIRI-Induced Microvascular
Exogenous tPA can be a robust driver of the self-reinforcing loop of gelatinase activation (Scheme 1.1). However, with the progression of cerebral ischemia, the gelatinase-mediated degradation of the ECM may lead to disruption of the microvascular bed and exposure of the brain parenchyma to the exogenous tPA.
5 Early Inhibition of Gelatinases May Escalate
Neuroprotection and Extend the tPA Therapeutic Window
Agrin accumulates in the brain microvascular basal lamina during blood-brain barrier development. Plasmin-dependent modulation of the blood-brain barrier: an important aspect during tpa-induced thrombolysis.
Characters of Ischemic Stroke and Recanalization Arteries
To understand the characteristics, especially the pathophysiology and recanalization of the artery, are very important to find potential therapeutic targets and improve the long-term outcomes of ischemic stroke in clinical practice.
2 Characters of the Ischemic Stroke
Epidemiology and Risk Factors of Ischemic Stroke
Controlling behavioral and metabolic risk factors could prevent about 75% of the global burden of stroke [13]. Another important risk factor is atrial fibrillation (AF), blood clots usually develop in the left atrial appendage.
The Imaging and Diagnosis of Ischemic Stroke
Typical symptoms of ischemic stroke include sudden unilateral weakness, numbness, or vision loss; diplopia; altered speech; ataxia; and non-orthostatic dizziness [24]. It was diagnosed as an acute ischemic stroke of the left basal ganglia. a) Left basal ganglia decreased CBF as the arrow indicates.
The Pathophysiology of Ischemic Stroke
- Excitotoxicity
- Inflammatory Response
- Apoptosis
- Autophagy
- Pyroptosis
In middle cerebral artery occlusion (MCAO)-induced ischemic stroke rats, the brain tissue expression level of IL-17 was elevated at 1 h after ischemic stroke and peaked at day 6 [48] . It is worthy to explore the role of pyroptosis in ischemic stroke models in depth.
3 Artery Recanalization of Ischemic Stroke
Intravenous Thrombolytic and Antiplatelet Therapy Treatment
In 2014, the research first reported that embryonic cortical neurons express a functional AIM2 inflammasome and identified pyroptosis as a cell death mechanism in neurons. It demonstrated pannexin1 as a cell death effector channel in pyroptosis and inhibition of pannexin1 by probenecid attenuated pyroptosis in neurons, suggesting that active Caspase-1 cleaves inflammatory cytokines, opens the pannexin1 pore and causes cell death [84].
Endovascular Treatment for Acute Ischemic Stroke
In recent years, some studies have focused on trials to evaluate whether ischemic stroke patients with small cores and substantial resolvable penumbra, as determined by CT or MR perfusion, could benefit from rt-PA and endovascular thrombectomies longer than 6 hours [90]. The EPITHET study is testing rt-PA given 3–6 hours after stroke onset, with PWI and DWI performed before and 3–5 days after therapy.
Antioxidant and Other Treatment
As a result of the mitochondrial lipid peroxidation, Ca2+ overloads so that mitochondrial membrane depolarization, which promotes cytochrome c to be released and leads to cell apoptosis [106-108]. On the other hand, hypothermia can protect the BBB integrity according to decreasing MMP proteolytic activity and degrading the components of the extracellular matrix that comprise the BBB [ 115 ].
4 Reperfusion Injury After Artery Recanalization
Leukocytes release lysozymes, produce reactive oxygen species, and release leukocyte chemotactic agents involved in the reperfusion injury process [122]. The activity of inducible nitric oxide synthase results from cerebral ischemia and the production of nitric oxide, acting as the main reactive oxide species, is involved in the process of necrosis and apoptosis [126].
5 Conclusion
Adamczak SE, de Rivero Vaccari JP, Dale G, Brand FJ III, Nonner D, Bullock MR, et al.
Cerebral Ischemic Reperfusion Injury (CIRI) Cases
1 Case Description
However, the patient's condition worsened 9 hours after onset (ie, 3 hours after recanalization), with sudden vomiting and slow pupillary light reflex. The patient was again given clopidogrel 75 mg/day the next day to prevent in-stent thrombosis.
2 Discussion
A review of the mechanisms of blood-brain barrier permeability by tissue-type plasminogen activator treatment for cerebral ischemia. Vascular enhancement and blood-cerebrospinal fluid barrier disruption after mechanical thrombectomy in acute ischemic stroke.
CIRI After Early Recanalization
1 Hemorrhage Transformation (HT)
Mechanisms
- Oxidative Stress
- Neurovascular Unit Injury
A rapid increase in the amount of ROS in ischemic mitochondria causes changes in the cytoskeleton and affects endothelial and epithelial cells - the permeability of the BBB. The basic second peak in the expression of important factors (such as MMP, IL-1, TNF-a) can influence the subsequent re-opening of the brain-blood barrier [17].
Predictive Imaging Markers
- Brain-Blood Barrier Permeability
- Postischemic Hyperperfusion
Approximately 48% of patients treated with reperfusion therapy had a significantly higher blood flow velocity (1.7 times on average) in or around areas of the ischemic core than on the contralateral side. Later hyperperfusion time was associated with a higher risk of HT (Spearman's rank correlation of 0.44, p = 0.003).
2 Infarct Growth
Mechanisms
- Apoptosis
- Neutrophil Infiltration and Immune Inflammation
Initial CTP (panel a) showed hypoperfusion in the left MCA compartment, and follow-up DWI and CBF (panel b, c) showed hyperperfusion of the left MCA and HT. A 43-year-old man presented with mild coma, aphasia, right-sided paralysis, and was found to have a left MCA stroke with a baseline NIHSS of 25.
Predictive Imaging Markers
- No-Reflow Phenomenon
- Cerebral Neutrophil Recruitment
- Vascular Inflammation
- Postischemic Hyperperfusion
Infusion of wild-type CD3 + T cells into Rag1 −/− mice rendered it vulnerable to ischemia/reperfusion injury [ 37 ]. Unfortunately, due to low contrast sensitivity, molecular imaging has its own limitation when imaging the status of endothelial inflammation after ischemia/reperfusion injury [42].
3 Brain Edema
Mechanisms and Edema Types
- Brain-Blood Barrier Damage and Vasogenic Edema
- Postischemic Hyperperfusion and Cytotoxic Edema
The blood brain barrier consists of endothelial cells, cerebral microvessels, capillary basement membranes, and glial cells [ 44 , 45 ]. Therefore, any mechanism that disrupts the stability of the blood-brain barrier as above will lead to vasogenic edema [29].
4 Treatments
Ischemic Conditioning Therapy
- Ischemic Preconditioning Therapy
- Ischemic Postconditioning Therapy
Administration with BMS-191095 24 h before the onset of 90 min transient ischemia in rats reduced total infarct volume by 32% and cortical infarct volume by 38%, whereas those treated 30 or 60 min before onset had no effect not. By performing three cycles of 30 s of common carotid artery (CCA) reperfusion and 10 s of CCA occlusion on the special stroke rat models, the final infarct volume decreased approximately 17–80%.
Immunosuppressive Agents
Previous study showed BMS-191095 was an opener of the selective ATP-sensitive potassium (mito KATP) channel [46]. According to his applied time course, there are rapid PostC (within a few seconds to minutes after reperfusion) and delayed PostC (within a few hours to days after reperfusion) [ 48 ].
Hypothermia Treatment
The blood-brain barrier is continuously open for several weeks after transient focal cerebral ischemia. Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue damage, blood-brain barrier damage, and edema formation.
Programmed Cell Death in CIRI
In ischemic injury, there were three main morphologies of programmed cell death, including type I, apoptosis; type II, autophagy; and type III, programmed necrosis (known as necroptosis) [5, 6]. Type II – autophagic cell death – is a catabolic process conserved in all eukaryotes from yeast to mammals; is the mechanism by which organelles are removed.
2 Apoptotic Cell Death in CIRI
Molecular Biology Mechanism of Apoptosis After Ischemic Stroke
- Molecules Related to Apoptosis of Neurons
In the early stages of cerebral infarction, caspase-8 and caspase-1 are involved in the early apoptosis, contributing to the nucleus. However, Caspase-9 is related to the secondary extension of the lesion in the penumbral area [18].
Pathways Related to Apoptosis of CIRI
- Intrinsic Pathway
- Extrinsic Pathway
In contrast, apoptosis-inducing factor (AIF) mediates cell death by a caspase-independent method, which is also released from the pore and rapidly translocates to the nucleus. Because of the initiating effect of death receptors on the plasma membrane, the extrinsic pathway is also called the receptor-mediated pathway.
Significance of Apoptosis in CIRI
The above process involving Bax and Bcl-2 is the critical event in the mitochondria-mediated pathway [ 31 ]. These findings indicate that death receptors are critically involved in the induction of apoptosis after ischemia in the adult brain and that their suppression can improve neuronal survival after ischemic injury [12, 40].
3 Necroptosis in CIRI
Signal Pathway of Necroptosis
In global cerebral ischemia in gerbils, treatment with a purified medicinal herb called baicalin remarkably promoted the expression of BDNF and inhibited the expression of caspase-3 at mRNA and protein levels [42]. PGAM5L binding to the necrosome is not affected by the presence of the necrosis inhibitor necrosulfonamide (NSA).
Necroptosis in Cerebral Ischemia Disease
Furthermore, mitochondrial fragmentation induced by the mitochondrial phosphatase PGAM5S recruited the mitochondrial fission factor Drp1 can up-regulate ROS generation [ 57 ].
The Regulation of Necroptosis in Cerebral Ischemic Model
4 Autophagic Cell Death in CIRI
Possible Autophagy Signaling Pathways in Cerebral Ischemia
The figure shows the many different signaling pathways involved in the activation of autophagy during cerebral ischemia. PPAR-γ activation antagonizes beclin-1-mediated autophagy via upregulation of Bcl-2/Bcl-xl, which interacts with beclin-1 in cerebral ischemia/reperfusion [84].
The Dual Roles of Autophagy in Cerebral Ischemia
- Detrimental Role of Autophagy in Ischemic Cerebral Injury
- Beneficial Role of Autophagy in Cerebral Ischemic Injury
117] suggested that in neonatal hypoxia-ischemia, autophagy may be part of an integrated pro-survival signaling complex involving PI3K-Akt-mTOR. When either the autophagy or PI3K-Akt-mTOR pathways were disrupted, cells underwent necrotic cell death.
The Factors Determining the Role of the Autophagy in Cerebral Ischemia
- The Degree of Autophagy Determines the Fate of Cells in Cerebral Ischemia
- The Time at Which Autophagy Is Induced Determines Its Role
- Autophagy May Be Interrupted in Cerebral Ischemia
The results indicated that the accumulation of autophagy-related proteins after ischemia may be the result of the failure of the autophagy pathway. Further studies are required to verify whether autophagy activity is increased in cerebral ischemia.
5 Crosstalk Between Apoptosis, Autophagy and Necroptosis (Necrosis) After CIRI
Regulatory role of nf-kappa in autophagy-like cell death after focal cerebral ischemia in mice. Propofol prevents cerebral ischemia-induced autophagy activation and cell death in rat hippocampus through nf-kappab/.
Reactive Astrocytes in Cerebral Ischemic Reperfusion Injury
Stroke is a leading cause of death worldwide, and in the United States alone its incidence is about 3% of the adult population. Astrocytes in the ischemic penumbra region show dysfunction and delayed death, while astrocytes directly in the core region of the cardiovascular bed are more likely to die earlier, as they cannot get blood supply from nearby arteries [8].
2 Astrocyte Function in Normal Brains
- Astrocytes “Save” Dying Neurons by Providing Them with Antioxidant Defense
- The Function of Glucose Transporters in Astrocytes
- Roles of Astrocytes in Synaptogenesis and Synaptic Pruning
- Astrocytes Affect Synaptic Transmission by Releasing Gliotransmitters
Research in the last two decades has focused on the role of astrocytes in synapse formation, modification and connection. Thus, maintenance of normal functions of astrocytes in an ischemic brain is crucial for ischemic brain recovery and function [2].
3 Reactive Astrocytes in Ischemic Reperfusion 3.1 Formation of Reactive Astrocytes
Altered Functions in Reactive Astrocyte
At present, these regeneration-inhibitory effects represent the disadvantages linked to other beneficial effects of reactive astrocytes. In particular, the effective management of the acute stage of an injury by reactive astrocytosis reduces cellular and tissue stress and provides effective neuroprotection together with the beneficial isolation of the lesion area from the rest of the CNS [55-57].
Impact of Reactive Astrocytes on Neural Protection and Repair
Reactive astrogliosis can lead to the appearance of newly proliferated astrocytes and scar formation in response to severe tissue damage or inflammation. Molecular triggers that lead to this scarring include epidermal growth factor (EGF), fibroblast growth factor (FGF), endothelin 1 and adenosine triphosphate (ATP).
Reactive Astrocytes in Regulation of Inflammation
Molecules produced by astrocytes that exert or regulate anti-inflammatory functions activate various anti-inflammatory signaling mechanisms. Loss-of-function transgenic approaches have begun to define the intracellular signaling cascades that mediate the anti-inflammatory functions of astrocytes.
4 Modulating Astrogliosis to Remove Detriments and Retain Benefits
Potential Targets for Improvement of Astrocyte Functions
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Role of the injury scar in the response to damage and repair of the central nervous system.
Oxidative Stress and Nitric Oxide
After cerebral ischemic reperfusion injury, favored by an overload of calcium in the cells, there is increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including superoxide anion (O2·−), hydrogen peroxide (H2O2), hydroxyl radical ( OH−), nitric oxide (NO··) or peroxynitrite (OONO−) in the mitochondria of the penumbral tissue [4, 5]. Because the ischemic brain is highly sensitive to oxidative and nitrosative damage, preventing the effects of ROS and RNS is a potential therapeutic strategy for the cerebral ischemic reperfusion injury [4, 6].
2 Oxidative Stress in Cerebral Ischemic Reperfusion Injury 2.1 Reactive Oxygen Species
- The Oxidative Stress Hypothesis
- Main Sources of Oxidative Stress in Cerebral Ischemic Reperfusion Injury
- NADPH Oxidase and Expression of NADPH in the Central Nervous System
- The Role of NADPH Oxidase in Cerebral Ischemic Reperfusion Injury
- Pharmacological Approaches to Inhibit NOX Activity
- Antioxidants Therapies
- Non-specific NOX Inhibitors
- Specific NOX Inhibitors
In addition, much evidence has shown that oxidative stress is a central element of the pathological development after cerebral ischemia reperfusion injury [20–23]. NOX1 has been shown to be expressed in the plasma membrane of vascular smooth muscle cells [63].
3 Nitrosative Stress in Cerebral Ischemic Reperfusion Injury 3.1 Reactive Nitrogen Species
Main Sources of Nitric Oxide
Nitric oxide (NO) is the signaling molecule primitively known as endothelium-derived relaxing factor (EDRF) that regulates relaxation of blood vessels [108]. NO derived from iNOS also has multiple functions, including contribution to the neurotoxic effects after ischemic stroke and traumatic brain injury and regulation of cerebral blood flow [113–115].
Roles of RNS in Cerebral Ischemic Reperfusion Injury
In contrast to the high concentration of NO from iNOS and eNOS, the low concentration of NO generated by eNOS exerts neuroprotective effects. During both the ischemic and reperfusion stages, the generation of ONOO is extremely increased due to the dramatically rapid generation of NO.
Pharmacological Approaches to Regulate RNS Activity
- Increasing eNOS Activity
- nNOS and iNOS Inhibition
- Increasing Substrates of NO Production
Furthermore, the antioxidant properties of statins also contribute to the reduction of oxidative stress in the brain after ischemic stroke [150]. NO donors and substrates of eNOS have been used to improve the prognosis of patients suffering from ischemic stroke for a long time.
4 Conclusion
Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. Nitric oxide regulates caveolin-1 expression in rat brain during focal cerebral ischemia and reperfusion injury.
Extracellular Matrix in Stroke
1 Extracellular Matrix
Interstitial Matrix
The interstitial matrix is a loose network mainly composed of fibrillar collagens, including collagen I, II, III, V, XI, XXIV, and XXVII, among which collagen I is the major form. The interstitial matrix is diffusely distributed between cells in the parenchyma and acts as scaffolding for tissues [8, 10].
Perineuronal Nets
- Collagen IV
- Laminin
- Nidogen
- Perlecan
These data suggest that nidogens function as a linker to connect collagen IV and laminin networks. Unlike collagen IV and laminin, perlecan is unable to form supramolecular sheet-like structures [81].
It should be noted that perlecan, especially its domains IV and V, can be recognized and cleaved by many proteases, including thrombin, plasmin and collagenase. Next, collagen IV networks are connected to laminin networks on the cell surface via nidogen bridging, forming a 3D scaffold.
- Collagen IV
- Laminin
- Nidogen
- Perlecan
Furthermore, ischemic stroke was detected in patients with mutations in the COL4A1 gene encoding the α1 chain of collagen IV. These data suggest that collagen IV may be involved in the pathogenesis of ischemic stroke.
6 Future Directions
Ultrastructural and temporal changes of the microvascular basement membrane and astrocyte interface after focal cerebral ischemia. Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, et al.
Inflammation and Ischemic Stroke
We will discuss the main cascades of inflammatory responses involved in cerebral ischemia and brain injury. Next, we will discuss the inflammatory cells involved in brain damage after stroke and clarify the relationship between neuroinflammation and brain repair.
2 Neuroinflammatory Triggers, Molecules,
As a result, both the activated microglia/macrophages and the infiltrated leukocytes secrete cytotoxic inflammatory mediators, such as matrix metalloproteinases (MMPs), nitric oxide (NO), cytokines, and ROS, increasing brain edema, promoting hemorrhagic transformation, and exacerbating neuronal death. We will first introduce the factors that initiate or cause neuroinflammation after stroke, and the associated cell signaling pathways during neuroinflammation.
DAMPs
146 . and E-select element) that are also released into the peripheral blood to stimulate the activation of peripheral leukocytes. DAMPs also induce activation of other PRRs such as receptors for advanced glycation end products (RAGE) and c-type lectin receptors [10].
Pattern-Recognition Receptor (PRR)
The activation of TLRs initiates signaling events that stimulate the production of pro-inflammatory cytokines and chemokines, leading to the recruitment of leukocytes, especially neutrophils and macrophages. The production of ROS and nitric oxide derivatives leads to the recruitment of leukocytes to the ischemic area, subsequently exaggerating the initial damage.
3 The Production of Inflammatory Molecules
- Cytokines
- Chemokines
- MMPs
- Cell Adhesion Molecules
CCL2 expression is induced in response to ischemic insult, and plays a key role in the recruitment of monocytes in ischemic tissue injury [28]. Recently, it has been widely reported that CCL5 induced the recruitment of leukocyte and platelet adhesion in the cerebral microvasculature [ 30 ].
4 Inflammatory Cells and Ischemic Stroke
Brain Resident Cells in Ischemic Stroke
Peripheral Blood-Borne Cells in Ischemic Stroke
Consequently, M1 macrophages promote brain injury, while M2 macrophages inhibit brain injury and promote brain recovery. Depletion of CD4 or CD8 T cells reduces brain damage; γδT cells promote brain injury, while Treg activity reduces brain injury and promotes functional recovery after stroke.
5 Post-ischemic Inflammation and Brain Repair
The Removal of Necrotic Cells
The crucial process in brain repair consists mainly of suppression of inflammation and clearance of dead cells [62], in which neutrophils and macrophages play a crucial role. Nevertheless, it has not been distinguished how microglia and monocyte-derived macrophages contribute to brain repair.
Oligodendrogenesis
Macrophages include monocytes and microglia-derived macrophages, which polarize into pro-inflammatory M1 and anti-inflammatory M2. Other PtdSer-binding proteins include MGF-E8 on microglia and TIM4 on macrophages, which also participate in the clearance of dead cells [ 65 ].
Angiogenesis
6 Anti-Inflammatory Therapy in Ischemic Stroke
Targeting Inflammasome Signaling Pathways
Targeting Neutrophil Recruitment
Immunosuppression Strategies
7 Summary
Epigallocatechin gallate expands the therapeutic window of recombinant tissue plasminogen activator therapy for cerebral ischemic stroke: a randomized double-blind and placebo-controlled trial. Therapeutic strategies to attenuate hemorrhagic transformation after tissue plasminogen activator therapy for acute ischemic stroke.
Cerebral Vascular Injury in Diabetic Ischemia and Reperfusion
1 Ischemia-Reperfusion Injury in Stroke
Disruption of the integrity of the blood-brain barrier (BBB) is one of the most important pathophysiological events after ischemic stroke. As one of the most well-known consequences of ischemia-reperfusion injury, hemorrhagic transformation can lead to poorer ischemic stroke outcomes.
2 Diabetic Ischemia and Reperfusion
Although recent animal studies provided very valuable information on ischemia-reperfusion injury, the involvement of human studies remains at an early stage, especially with regard to the dynamic course of reperfusion-induced brain injury and clinical characteristics of acute ischemic stroke. A clinical study that included 58,265 patients with acute ischemic stroke treated with tPA showed that both acute and chronic hyperglycemia are related to increased mortality and poor clinical outcomes [17].
3 Mechanisms of Cerebral Vascular Injury in Diabetic Ischemia and Reperfusion
In another diabetic animal model, the Goto-Kakizaki (GK) rat model, Elgebaly MM et al. Autophagy protects human brain microvascular endothelial cells against methylglyoxal-induced injuries, reproducibly in a cerebral ischemic model in diabetic rats.
Ischemia/Reperfusion Damage in Diabetic Stroke
1 Epidemiology
Approximately 30% of patients with acute stroke suffer from pre-existing diabetes or newly diagnosed diabetes [4, 5]. The poor prognosis in diabetic stroke patients may be at least partially attributed to exacerbated stroke pathology and ischemia-reperfusion (I/R) injury [ 9 , 10 ].
2 Ischemia/Reperfusion Damage in Diabetic Stroke 2.1 Reperfusion Strategies After Stroke
Challenges in Reperfusion Treatments After Stroke
Patients for tPA therapy even within the time frame 0-3 hours should be carefully selected and exclusion criteria include patients who are susceptible to intracerebral hemorrhage, patients who have suffered a stroke or traumatic brain injury in the previous 3 months , patients consuming anticoagulants, etc. In addition, exclusion criteria for using tPA in the 3-4.5 hour time period include patients older than 80 years, patients consuming oral anticoagulants, patients with a history of stroke and DM, and patients sustaining severe stroke with ischemic damage in more than one third of the territory of the middle cerebral artery [18].
I/R injury in Diabetic Stroke
The biggest challenge of tPA treatment in stroke care is the short time frame for initiating treatment. The efficacy of tPA treatment also depends on the stroke subtype, and in DM stroke a large number of stroke patients suffer from large vessel atherothrombotic stroke, for which tPA treatment is less efficient compared to other subtypes of stroke [29].
3 Pathophysiology of I/R Injury in Diabetic Stroke
Neurovascular Uncoupling After I/R Injury in Diabetic Stroke
Neurovascular uncoupling and BBB disruption are among the initial steps of the pathophysiological cascade in diabetes and stroke [33]. Stroke in patients with diabetes exacerbates BBB disruption; and BBB permeability, which normally increases within 7 days after stroke under non-diabetic conditions, was prolonged to 14 days or longer in stroke animals [36–38] .
Edema in Diabetic Stroke
In the acute phase of stroke, reactive astrocytes secrete pro-inflammatory cytokines, inhibit axonal regeneration and assist in infarct expansion [47]. During the chronic phase after stroke, reactive astrocytes aid in neurite sprouting, synapse formation, BBB rebuilding, and secrete neurotrophic factors that aid in brain repair mechanisms [46, 47].
Hemorrhagic Transformation in Diabetic Stroke
4 Mechanisms of I/R Injury in Diabetic Stroke 4.1 Impaired Angiogenic Signaling
- Altered Vascular Shear Stress
- High Insulin Resistance and Diminished Fibrinolysis
- Mitochondrial Dysfunction and Oxidative Stress
- Inflammatory Responses
- Extracellular Membrane Vesicles
- MicroRNAs (MiRs)
- Gut-Brain Axis
In DM stroke, mitochondrial oxidative stress and an abundant increase in reactive oxygen species (ROS) are key mediators of pathological changes [ 44 ]. In DM mice subjected to I/R stroke model, HMGB1 promotes inflammation by increasing the expression of cytokines such as interleukins (IL-1β, IL-6) and inflammation-related enzyme inducible nitric oxide synthase (iNOS), which then leads to secondary brain injury [102].
5 Summary
Epidemiology of ischemic stroke in patients with diabetes: the larger Cincinnati/Northern Kentucky stroke study. Guidelines for the Early Management of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association.
