International Journal of Molecular Sciences

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Open AccessEditorial

Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives

by Anna Bersano and Laura Gatti

Int. J. Mol. Sci. 2023, 24(19), 14848; https://doi.org/10.3390/ijms241914848 - 3 Oct 2023

Cited by 12 | Viewed by 3953

Abstract

Stroke is among the most prevalent causes of disability and is the second leading cause of death worldwide in Western countries [...] Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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13 pages, 3773 KiB

Open AccessArticle

Immunohistological Analysis of Neutrophils and Neutrophil Extracellular Traps in Human Thrombemboli Causing Acute Ischemic Stroke

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

Int. J. Mol. Sci. 2020, 21(19), 7387; https://doi.org/10.3390/ijms21197387 - 7 Oct 2020

Cited by 44 | Viewed by 3722

Abstract

Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium [...] Read more.

Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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13 pages, 2154 KiB

Open AccessArticle

Neuroprotective Effects of Emodin against Ischemia/Reperfusion Injury through Activating ERK-1/2 Signaling Pathway

by Stephen Wan Leung, Jing Huei Lai, John Chung-Che Wu, Yan-Rou Tsai, Yen-Hua Chen, Shuo-Jhen Kang, Yung-Hsiao Chiang, Cheng-Fu Chang and Kai-Yun Chen

Int. J. Mol. Sci. 2020, 21(8), 2899; https://doi.org/10.3390/ijms21082899 - 21 Apr 2020

Cited by 72 | Viewed by 3894

Abstract

Background: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, [...] Read more.

Background: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. Methods: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. Results: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. Conclusion: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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16 pages, 2688 KiB

Open AccessArticle

FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARγ Activation

by Yinghua Jiang, Li Lin, Ning Liu, Qingzhi Wang, Jing Yuan, Yadan Li, Kelly K. Chung, Shuzhen Guo, Zhanyang Yu and Xiaoying Wang

Int. J. Mol. Sci. 2020, 21(3), 824; https://doi.org/10.3390/ijms21030824 - 28 Jan 2020

Cited by 41 | Viewed by 4924

Abstract

Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood–brain barrier (BBB) damage in T2DM mice [...] Read more.

Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood–brain barrier (BBB) damage in T2DM mice via peroxisome proliferator-activated receptor gamma (PPARγ) activation in cerebral microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) model in T2DM mice as well as cultured human brain microvascular endothelial cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current study. We detected a significant reduction in PPARγ DNA-binding activity in the brain tissue and mRNA levels of BBB junctional proteins and PPARγ-targeting gene CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke induced a massive BBB leakage two days after stroke in T2DM mice compared to in their lean controls. Importantly, all abnormal changes were significantly prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro experimental results also demonstrated that rFGF21 protects against hyperglycemia plus interleukin (IL)-1β-induced transendothelial permeability through upregulation of junction protein expression in an FGFR1 activation and PPARγ activity elevation-dependent manner. Our data suggested that rFGF21 has strong protective effects on acute BBB leakage after diabetic stroke, which is partially mediated by increasing PPARγ DNA-binding activity and mRNA expression of BBB junctional complex proteins. Together with our previous investigations, rFGF21 might be a promising candidate for treating diabetic stroke. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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Review

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17 pages, 937 KiB

Open AccessReview

Soluble Receptors Affecting Stroke Outcomes: Potential Biomarkers and Therapeutic Tools

by Ayon Bhattacharya, Rani Ashouri, Madison Fangman, Alexandra Mazur, Timothy Garett and Sylvain Doré

Int. J. Mol. Sci. 2021, 22(3), 1108; https://doi.org/10.3390/ijms22031108 - 23 Jan 2021

Cited by 9 | Viewed by 3625

Abstract

Soluble receptors are widely understood to be freestanding moieties formed via cleavage from their membrane-bound counterparts. They have unique structures, are found among various receptor families, and have intriguing mechanisms of generation and release. Soluble receptors’ ability to exhibit pleiotropic action by receptor [...] Read more.

Soluble receptors are widely understood to be freestanding moieties formed via cleavage from their membrane-bound counterparts. They have unique structures, are found among various receptor families, and have intriguing mechanisms of generation and release. Soluble receptors’ ability to exhibit pleiotropic action by receptor modulation or by exhibiting a dual role in cytoprotection and neuroinflammation is concentration dependent and has continually mystified researchers. Here, we have compiled findings from preclinical and clinical studies to provide insights into the role of soluble/decoy receptors, focusing on the soluble cluster of differentiation 36, the soluble cluster of differentiation 163, and soluble lipoprotein-related protein 1 (sCD36, sCD163, and sLRP1, respectively) and the functions they could likely serve in the management of stroke, as they would notably regulate the bioavailability of the hemoglobin and heme after red blood cell lysis. The key roles that these soluble receptors play in inflammation, oxidative stress, and the related pharmacotherapeutic potential in improving stroke outcomes are described. The precise pleiotropic physiological functions of soluble receptors remain unclear, and further scientific investigation/validation is required to establish their respective role in diagnosis and therapy. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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30 pages, 861 KiB

Open AccessReview

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

by Marc Melià-Sorolla, Carlos Castaño, Núria DeGregorio-Rocasolano, Luis Rodríguez-Esparragoza, Antoni Dávalos, Octavi Martí-Sistac and Teresa Gasull

Int. J. Mol. Sci. 2020, 21(18), 6568; https://doi.org/10.3390/ijms21186568 - 8 Sep 2020

Cited by 12 | Viewed by 4751

Abstract

In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated [...] Read more.

In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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15 pages, 1351 KiB

Open AccessReview

Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review

by Masahiro Hatakeyama, Itaru Ninomiya, Yutaka Otsu, Kaoru Omae, Yasuko Kimura, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata and Masato Kanazawa

Int. J. Mol. Sci. 2020, 21(17), 6194; https://doi.org/10.3390/ijms21176194 - 27 Aug 2020

Cited by 21 | Viewed by 5928

Abstract

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are [...] Read more.

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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17 pages, 2504 KiB

Open AccessReview

Lessons from Recent Advances in Ischemic Stroke Management and Targeting Kv2.1 for Neuroprotection

by Chung-Yang Yeh, Anthony J. Schulien, Bradley J. Molyneaux and Elias Aizenman

Int. J. Mol. Sci. 2020, 21(17), 6107; https://doi.org/10.3390/ijms21176107 - 25 Aug 2020

Cited by 12 | Viewed by 5321

Abstract

Achieving neuroprotection in ischemic stroke patients has been a multidecade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently, however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In [...] Read more.

Achieving neuroprotection in ischemic stroke patients has been a multidecade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently, however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We further summarize the results available thus far for nerinetide, a promising neuroprotective agent for stroke treatment. Lastly, we reflect upon aspects of these impactful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We argue that recent changes in the clinical landscape should be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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20 pages, 681 KiB

Open AccessReview

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy

by Laura Gatti, Francesca Tinelli, Emma Scelzo, Francesco Arioli, Giuseppe Di Fede, Laura Obici, Leonardo Pantoni, Giorgio Giaccone, Paola Caroppo, Eugenio Agostino Parati and Anna Bersano

Int. J. Mol. Sci. 2020, 21(10), 3435; https://doi.org/10.3390/ijms21103435 - 13 May 2020

Cited by 46 | Viewed by 7959

Abstract

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, [...] Read more.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as ‘the prion hypothesis’ have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression. Full article

(This article belongs to the Special Issue Pathophisiology and Treatment of Stroke: Present Status and Future Perspective)

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