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Cellular and Molecular Targets in Acute Ischemic Stroke

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 29155

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Dr. Peter Kraft

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Guest Editor

Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany
Interests: pathogenesis of ischemic stroke with focus on processes of thrombo-inflammation and cerebral I/R injury; biomarker-studies in clinical stroke; identification of novel treatment targets in experimental/human ischemic stroke; care research in stroke

Dr. Michael Schuhmann

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Guest Editor

Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany
Interests: to understand the mechanisms underlying penumbral tissue loss during vascular occlusion and of I/R injury thereafter in stroke

Special Issue Information

Dear Colleagues,

Despite the various treatment strategies available, ischemic stroke (IS) is still a leading cause of death and disability worldwide. Therefore, scientists are trying to identify novel cellular and molecular targets that might be developed for clinical treatment applications in the future. Until two decades ago, IS was mainly understood as the prototype of mere thrombotic disease; however, nowadays there is clear evidence that IS rather involves the whole neurovascular unit (including endothelial cells, neurons, astrocytes, myocytes, pericytes and extracellular matrix components) and interactions with immune cells. Innovation in this area of research has led to remarkable discoveries and improved understanding of the pathophysiology of IS. Nevertheless, more work and a tenacious pursuit of the basic/clinical sciences in cerebrovascular pathophysiology and pharmacology are still necessary. The aim of this Special Issue is to present the current knowledge of “Cellular and Molecular Targets in Acute Ischemic Stroke”, which might provide potential treatment strategies for future use. Therefore, we wish to invite researchers worldwide to contribute to this Special Issue. We encourage contribution by original research articles, as well as review articles (basic molecular/cellular studies; clinical studies examining molecular/cellular targets; no pure clinical studies out of that focus).

Dr. Peter Kraft
Dr. Michael Schuhmann
Guest Editors

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Keywords

ischemic stroke
thrombosis
inflammation
pathophysiology
blood–brain barrier
neurovascular unit
platelet
translational research
neuroprotection
drug development

Published Papers (12 papers)

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Editorial

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2 pages, 163 KiB

Open AccessEditorial

Cellular and Molecular Targets in Acute Ischemic Stroke

by Peter Kraft and Michael K. Schuhmann

Int. J. Mol. Sci. 2022, 23(19), 11097; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911097 - 21 Sep 2022

Cited by 1 | Viewed by 823

Abstract

Despite the available treatment strategies, ischemic stroke (IS) is still a leading cause of death and disability worldwide [...] Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

Research

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13 pages, 2368 KiB

Open AccessArticle

Regulation and Release of Vasoactive Endoglin by Brain Endothelium in Response to Hypoxia/Reoxygenation in Stroke

by Axel Haarmann, Lena Zimmermann, Michael Bieber, Christine Silwedel, Guido Stoll and Michael K. Schuhmann

Int. J. Mol. Sci. 2022, 23(13), 7085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137085 - 25 Jun 2022

Cited by 5 | Viewed by 1906

Abstract

In large vessel occlusion stroke, recanalization to restore cerebral perfusion is essential but not necessarily sufficient for a favorable outcome. Paradoxically, in some patients, reperfusion carries the risk of increased tissue damage and cerebral hemorrhage. Experimental and clinical data suggest that endothelial cells, representing the interface for detrimental platelet and leukocyte responses, likely play a crucial role in the phenomenon referred to as ischemia/reperfusion (I/R)-injury, but the mechanisms are unknown. We aimed to determine the role of endoglin in cerebral I/R-injury; endoglin is a membrane-bound protein abundantly expressed by endothelial cells that has previously been shown to be involved in the maintenance of vascular homeostasis. We investigated the expression of membranous endoglin (using Western blotting and RT-PCR) and the generation of soluble endoglin (using an enzyme-linked immunosorbent assay of cell culture supernatants) after hypoxia and subsequent reoxygenation in human non-immortalized brain endothelial cells. To validate these in vitro data, we additionally examined endoglin expression in an intraluminal monofilament model of permanent and transient middle cerebral artery occlusion in mice. Subsequently, the effects of recombinant human soluble endoglin were assessed by label-free impedance-based measurement of endothelial monolayer integrity (using the xCELLigence DP system) and immunocytochemistry. Endoglin expression is highly inducible by hypoxia in human brain endothelial monolayers in vitro, and subsequent reoxygenation induced its shedding. These findings were corroborated in mice during MCAO; an upregulation of endoglin was displayed in the infarcted hemispheres under occlusion, whereas endoglin expression was significantly diminished after transient MCAO, which is indicative of shedding. Of note is the finding that soluble endoglin induced an inflammatory phenotype in endothelial monolayers. The treatment of HBMEC with endoglin resulted in a decrease in transendothelial resistance and the downregulation of VE-cadherin. Our data establish a novel mechanism in which hypoxia triggers the initial endothelial upregulation of endoglin and subsequent reoxygenation triggers its release as a vasoactive mediator that, when rinsed into adjacent vascular beds after recanalization, can contribute to cerebral reperfusion injury. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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15 pages, 2356 KiB

Open AccessArticle

The Regulatory Role of H19/miR-181a/ATG5 Signaling in Perinatal Nicotine Exposure-Induced Development of Neonatal Brain Hypoxic-Ischemic Sensitive Phenotype

by Yong Li, Yanyan Zhang, Andrew Walayat, Yingjie Fu, Bailin Liu, Lubo Zhang and Daliao Xiao

Int. J. Mol. Sci. 2022, 23(13), 6885; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136885 - 21 Jun 2022

Cited by 5 | Viewed by 1646

Abstract

Nicotine exposure either from maternal cigarette smoking or e-cigarette vaping is one of the most common risk factors for neurodevelopmental disease in offspring. Previous studies revealed that perinatal nicotine exposure programs a sensitive phenotype to neonatal hypoxic-ischemic encephalopathy (HIE) in postnatal life, yet the underlying mechanisms remain undetermined. The goal of the present study was to determine the regulatory role of H19/miR-181a/ATG5 signaling in perinatal nicotine exposure-induced development of neonatal brain hypoxic-ischemic sensitive phenotype. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. All experiments were conducted in offspring pups at postnatal day 9 (P9). Perinatal nicotine exposure significantly enhanced expression of miR-181a but attenuated autophagy-related protein 5 (ATG5) mRNA and protein levels in neonatal brains. Of interest, miR-181a mimicking administration in the absence of nicotine exposure also produced dose-dependent increased hypoxia/ischemia (H/I)-induced brain injury associated with a decreased ATG5 expression, closely resembling perinatal nicotine exposure-mediated effects. Locked nucleic acid (LNA)-miR-181a antisense reversed perinatal nicotine-mediated increase in H/I-induced brain injury and normalized aberrant ATG5 expression. In addition, nicotine exposure attenuated a long non-coding RNA (lncRNA) H19 expression level. Knockdown of H19 via siRNA increased the miR-181a level and enhanced H/I-induced neonatal brain injury. In conclusion, the present findings provide a novel mechanism that aberrant alteration of the H19/miR-181a/AGT5 axis plays a vital role in perinatal nicotine exposure-mediated ischemia-sensitive phenotype in offspring and suggests promising molecular targets for intervention and rescuing nicotine-induced adverse programming effects in offspring. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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23 pages, 13607 KiB

Open AccessArticle

Regionally Altered Immunosignals of Surfactant Protein-G, Vascular and Non-Vascular Elements of the Neurovascular Unit after Experimental Focal Cerebral Ischemia in Mice, Rats, and Sheep

by Dominik Michalski, Willi Reimann, Emma Spielvogel, Bianca Mages, Bernd Biedermann, Henryk Barthel, Björn Nitzsche, Stefan Schob and Wolfgang Härtig

Int. J. Mol. Sci. 2022, 23(11), 5875; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115875 - 24 May 2022

Cited by 2 | Viewed by 1515

Abstract

The surfactant protein-G (SP-G) has recently been discovered in the brain and linked to fluid balance regulations. Stroke is characterized by impaired vessel integrity, promoting water influx and edema formation. The neurovascular unit concept (NVU) has been generated to cover not only ischemic affections of neurons or vessels but also other regionally associated cells. This study provides the first spatio-temporal characterization of SP-G and NVU elements after experimental stroke. Immunofluorescence labeling was applied to explore SP-G, vascular and cellular markers in mice (4, 24, and 72 h of ischemia), rats (24 h of ischemia), and sheep (two weeks of ischemia). Extravasated albumin indicated vascular damage within ischemic areas. Quantifications revealed decreasing SP-G signals in the ischemia-affected neocortex and subcortex. Inverse immunosignals of SP-G and vascular elements existed throughout all models. Despite local associations between SP-G and the vasculature, a definite co-localization was not seen. Along with a decreased SP-G-immunoreactivity in ischemic areas, signals originating from neurons, glial elements, and the extracellular matrix exhibited morphological alterations or changed intensities. Collectively, this study revealed regional alterations of SP-G, vascular, and non-vascular NVU elements after ischemia, and may thus stimulate the discussion about the role of SP-G during stroke. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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14 pages, 1869 KiB

Open AccessArticle

The Association between Hypoxia-Induced Low Activity and Apoptosis Strongly Resembles That between TTX-Induced Silencing and Apoptosis

by Domitilla Taxis di Bordonia e Valnigra, Gerco C. Hassink, Marloes R. Levers, Monica Frega, Jeannette Hofmeijer, Michel J. A. M. van Putten and Joost le Feber

Int. J. Mol. Sci. 2022, 23(5), 2754; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052754 - 02 Mar 2022

Cited by 4 | Viewed by 1725

Abstract

In the penumbra of a brain infarct, neurons initially remain structurally intact, but perfusion is insufficient to maintain neuronal activity at physiological levels. Improving neuronal recovery in the penumbra has large potential to advance recovery of stroke patients, but penumbral pathology is incompletely understood, and treatments are scarce. We hypothesize that low activity in the penumbra is associated with apoptosis and thus contributes to irreversible neuronal damage. We explored the putative relationship between low neuronal activity and apoptosis in cultured neurons exposed to variable durations of hypoxia or TTX. We combined electrophysiology and live apoptosis staining in 42 cultures, and compared effects of hypoxia and TTX silencing in terms of network activity and apoptosis. Hypoxia rapidly reduced network activity, but cultures showed limited apoptosis during the first 12 h. After 24 h, widespread apoptosis had occurred. This was associated with full activity recovery observed upon reoxygenation within 12 h, but not after 24 h. Similarly, TTX exposure strongly reduced activity, with full recovery upon washout within 12 h, but not after 24 h. Mean temporal evolution of apoptosis in TTX-treated cultures was the same as in hypoxic cultures. These results suggest that prolonged low activity may be a common factor in the pathways towards apoptosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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7 pages, 1797 KiB

Open AccessArticle

High Mobility Group Box 1 Protein in Cerebral Thromboemboli

by Fabian Essig, Lilith Babilon, Christoph Vollmuth, Alexander M. Kollikowski, Mirko Pham, László Solymosi, Karl Georg Haeusler, Peter Kraft, Guido Stoll and Michael K. Schuhmann

Int. J. Mol. Sci. 2021, 22(20), 11276; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011276 - 19 Oct 2021

Cited by 3 | Viewed by 1609

Abstract

High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6–6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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13 pages, 5032 KiB

Open AccessArticle

Treatment with Edoxaban Attenuates Acute Stroke Severity in Mice by Reducing Blood–Brain Barrier Damage and Inflammation

by Michael Bieber, Kathrin I. Foerster, Walter E. Haefeli, Mirko Pham, Michael K. Schuhmann and Peter Kraft

Int. J. Mol. Sci. 2021, 22(18), 9893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189893 - 13 Sep 2021

Cited by 6 | Viewed by 3045

Abstract

Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood–brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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14 pages, 2151 KiB

Open AccessArticle

Immune Cells Invade the Collateral Circulation during Human Stroke: Prospective Replication and Extension

by Marc Strinitz, Mirko Pham, Alexander G. März, Jörn Feick, Franziska Weidner, Marius L. Vogt, Fabian Essig, Hermann Neugebauer, Guido Stoll, Michael K. Schuhmann and Alexander M. Kollikowski

Int. J. Mol. Sci. 2021, 22(17), 9161; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179161 - 25 Aug 2021

Cited by 10 | Viewed by 1629

Abstract

It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R² = 0.09696, p = 0.0373) and (4) greater infarct extent (R² = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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17 pages, 33605 KiB

Open AccessArticle

Transient Global Ischemia-Induced Brain Inflammatory Cascades Attenuated by Targeted Temperature Management

by Dae Ki Hong, Yoo Seok Park, Ji Sun Woo, Ju Hee Kim, Jin Ho Beom, Sung Phil Chung, Je Sung You and Sang Won Suh

Int. J. Mol. Sci. 2021, 22(10), 5114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105114 - 12 May 2021

Cited by 4 | Viewed by 2616

Abstract

Sudden cardiac arrest leads to a significantly increased risk of severe neurological impairment and higher mortality rates in survivors due to global brain tissue injury caused by prolonged whole-body ischemia and reperfusion. The brain undergoes various deleterious cascading events. Among these damaging mechanisms, neuroinflammation plays an especially crucial role in the exacerbation of brain damage. Clinical guidelines indicate that 33 °C and 36 °C are both beneficial for targeted temperature management (TTM) after cardiac arrest. To clarify the mechanistic relationship between TTM and inflammation in transient global ischemia (TGI) and determine whether 36 °C produces a neuroprotective effect comparable to 33 °C, we performed an experiment using a rat model. We found that TTM at 36 °C and at 33 °C attenuated neuronal cell death and apoptosis, with significant improvements in behavioral function that lasted for up to 72 h. TTM at 33 °C and 36 °C suppressed the propagation of inflammation including the release of high mobility group box 1 from damaged cells, the activation and polarization of the microglia, and the excessive release of activated microglia-induced inflammatory cytokines. There were equal neuroprotective effects for TTM at 36 °C and 33 °C. In addition, hypothermic complications and should be considered safe and effective after cardiac arrest. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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13 pages, 3297 KiB

Open AccessArticle

The Effects of Atorvastatin on Global Cerebral Ischemia-Induced Neuronal Death

by A Ra Kho, Dae Ki Hong, Beom Seok Kang, Woo-Jung Park, Kyung Chan Choi, Kyoung-Ha Park and Sang Won Suh

Int. J. Mol. Sci. 2021, 22(9), 4385; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094385 - 22 Apr 2021

Cited by 6 | Viewed by 1963

Abstract

(1) Background and Purpose: Global cerebral ischemia-induced severe hypoxic brain damage is one of the main causes of mortality and long-term neurologic disability even after receiving early blood reperfusion. This study aimed to test the hypothesis that atorvastatin potentially has neuroprotective effects in global cerebral ischemia (GCI). (2) Methods: We performed two sets of experiments, analyzing acute (1-week) and chronic (4-week) treatments. For the vehicle (Veh) and statin treatments, 1 mL of 0.9% saline and 5 mg/kg of atorvastatin (ATOR) were administered orally. For histological analysis, we used the following staining protocols: Fluoro-Jade B and NeuN, 4-hydroxynonenal, CD11b and GFAP, IgG, SMI71, and vWF. Finally, we evaluated the cognitive function with a battery of behavioral tests. (3) Results: The GCI-ATOR group showed significantly reduced neuronal death, oxidative stress, inflammation, and BBB disruption compared with the GCI-Veh group. Moreover, the GCI-ATOR group showed decreased endothelial damage and VV proliferation and had significantly improved cognitive function compared with the GCI-Veh group in both models. (4) Conclusions: ATOR has neuroprotective effects and helps recover the cognitive function after GCI in rats. Therefore, administration of atorvastatin may be a therapeutic option in managing GCI after CA. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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Review

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36 pages, 4469 KiB

Open AccessReview

Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke

by Gelu Onose, Aurelian Anghelescu, Dan Blendea, Vlad Ciobanu, Cristina Daia, Florentina Carmen Firan, Mihaela Oprea, Aura Spinu, Cristina Popescu, Anca Ionescu, Ștefan Busnatu and Constantin Munteanu

Int. J. Mol. Sci. 2022, 23(2), 907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020907 - 14 Jan 2022

Cited by 35 | Viewed by 6256

Abstract

BACKGROUND: Cerebral circulation delivers the blood flow to the brain through a dedicated network of sanguine vessels. A healthy human brain can regulate cerebral blood flow (CBF) according to any physiological or pathological challenges. The brain is protected by its self-regulatory mechanisms, which are dependent on neuronal and support cellular populations, including endothelial ones, as well as metabolic, and even myogenic factors. OBJECTIVES: Accumulating data suggest that “non-pharmacological” approaches might provide new opportunities for stroke therapy, such as electro-/acupuncture, hyperbaric oxygen therapy, hypothermia/cooling, photobiomodulation, therapeutic gases, transcranial direct current stimulations, or transcranial magnetic stimulations. We reviewed the recent data on the mechanisms and clinical implications of these non-pharmaceutical treatments. METHODS: To present the state-of-the-art for currently available non-invasive, non-pharmacological-related interventions in acute ischemic stroke, we accomplished this synthetic and systematic literature review based on the Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses (PRISMA). RESULTS: The initial number of obtained articles was 313. After fulfilling the five steps in the filtering/selection methodology, 54 fully eligible papers were selected for synthetic review. We enhanced our documentation with other bibliographic resources connected to our subject, identified in the literature within a non-standardized search, to fill the knowledge gaps. Fifteen clinical trials were also identified. DISCUSSION: Non-invasive, non-pharmacological therapeutic/rehabilitative interventions for acute ischemic stroke are mainly holistic therapies. Therefore, most of them are not yet routinely used in clinical practice, despite some possible beneficial effects, which have yet to be supplementarily proven in more related studies. Moreover, few of the identified clinical trials are already completed and most do not have final results. CONCLUSIONS: This review synthesizes the current findings on acute ischemic stroke therapeutic/rehabilitative interventions, described as non-invasive and non-pharmacological. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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29 pages, 1905 KiB

Open AccessReview

Hypoxia Tolerant Species: The Wisdom of Nature Translated into Targets for Stroke Therapy

by Carmen del Río and Joan Montaner

Int. J. Mol. Sci. 2021, 22(20), 11131; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011131 - 15 Oct 2021

Cited by 4 | Viewed by 2927

Abstract

Human neurons rapidly die after ischemia and current therapies for stroke management are limited to restoration of blood flow to prevent further brain damage. Thrombolytics and mechanical thrombectomy are the available reperfusion treatments, but most of the patients remain untreated. Neuroprotective therapies focused on treating the pathogenic cascade of the disease have widely failed. However, many animal species demonstrate that neurons can survive the lack of oxygen for extended periods of time. Here, we reviewed the physiological and molecular pathways inherent to tolerant species that have been described to contribute to hypoxia tolerance. Among them, Foxo3 and Eif5A were reported to mediate anoxic survival in Drosophila and Caenorhabditis elegans, respectively, and those results were confirmed in experimental models of stroke. In humans however, the multiple mechanisms involved in brain cell death after a stroke causes translation difficulties to arise making necessary a timely and coordinated control of the pathological changes. We propose here that, if we were able to plagiarize such natural hypoxia tolerance through drugs combined in a pharmacological cocktail it would open new therapeutic opportunities for stroke and likely, for other hypoxic conditions. Full article

(This article belongs to the Special Issue Cellular and Molecular Targets in Acute Ischemic Stroke)

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