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Special Issue "Immunoinflammatory Background of Neuronal Damage in Stroke"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 September 2020).

Special Issue Editors

Prof. Dr. Antonino Tuttolomondo
E-Mail Website
Guest Editor
Biomedical Department of Internal Medicine and Medical Specialties (Di.Bi.M.I.S), University of Palermo, Palermo, Italy
Interests: ischemic stroke in diabetes; diabetic foot; Anderson-Fabry disease; cytokines
Special Issues, Collections and Topics in MDPI journals
Dr. Mario Daidone
E-Mail Website
Guest Editor
Università degli Studi di Palermo, Palermo, Italy

Special Issue Information

Dear Colleagues,

Ischemic stroke is caused by a reduction in blood flow to the brain, and it is a major cause of mortality and disability worldwide.

The most upstream consequence of cerebral ischemia, fundamentally, is composed of an energetic problem. Once this initial step has taken place, an ischemic cascade follows, involving a multimodal and multicell series of downstream mechanisms.

Inflammation is an important part of stroke pathophysiology, especially in the context of reperfusion. Several studies have shown that a nonspecific systemic inflammatory response occurs after both ischemic and hemorrhagic stroke, proving that inflammatory mechanisms intrinsic to the brain and the blood are among the important mediators of focal cerebral injury. The immune system is actively involved in the pathogenesis of acute brain damage through some events, such as leukocyte and monocyte infiltration into the brain; the activation of resident cells, including microglia, astrocytes, and endothelial cells; and several high serum levels.

Animal models of focal ischemia induced by middle cerebral artery occlusion (MCAO) provide evidence for most of the cellular inflammatory responses in stroke.

We will review the role of inflammatory cytokines in the pathogenesis of ischemic neuronal damage. We will also review the involvement of microglial, which are the major resident immune cells in CNS, and play a critical role in the immune response to a variety of events including infection, trauma, stroke, and neurogeneration. Among the various types of circulating leukocytes, neutrophils are generally the first leukocyte subtype recruited to the ischemic brain, and we will review their role in ischemic stroke pathogenesis. The inflammatory responses of the brain to post ischemia are characterized by the involvement of different subtypes of T lymphocytes, which contribute to the pathogenesis of stroke-induced microvascular dysfunction and tissue damage. We also will review the role of T lymphocytes and of their subsets. T cells can be separated into three major groups based on function, as follows: cytotoxic T cells (CD8+), helper T cells (Th; CD4+), and regulatory T cells (Tregs). We will review the literature on the available data concerning their involvement in ischemic stroke pathogenesis. We will also review the role of inflammatory mediators in a particular subtype of ischemic stroke, such as cardioembolic and atherosclerotic ones.

Prof. Dr. Antonino Tuttolomondo
Guest Editor

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Published Papers (6 papers)

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Research

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Article
Low Intensity Pulsed Ultrasound Prevents Recurrent Ischemic Stroke in a Cerebral Ischemia/Reperfusion Injury Mouse Model via Brain-derived Neurotrophic Factor Induction
Int. J. Mol. Sci. 2019, 20(20), 5169; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205169 - 18 Oct 2019
Cited by 5 | Viewed by 1150
Abstract
The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this [...] Read more.
The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this study, we hypothesized that LIPUS treatment possessed therapeutic benefits for the improvement of stroke recurrence. Adult male C57BL/6J mice were subjected to a middle cerebral artery occlusion (MCAO) surgery and then followed to secondary MCAO surgery as a stroke recurrence occurred after nine days from the first MCAO. LIPUS was administered continuously for nine days before secondary MCAO. LIPUS treatment not only decreased the mortality but also significantly moderated neuronal function injury including neurological score, motor activity, and brain pathological score in the recurrent stroke mice. Furthermore, the administration of LIPUS attenuated the apoptotic neuronal cells and increased Bax/Bcl-2 protein expression ratio and accelerated the expression of BDNF in the brain of the recurrent stroke mice. Taken together, these results demonstrate for the first time that LIPUS treatment arouses the expression of BDNF and possesses a therapeutic benefit for the improvement of stroke recurrence in a mouse model. The neuroprotective potential of LIPUS may provide a useful strategy for the prevention of a recurrent stroke. Full article
(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)
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Review

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Review
Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke
Int. J. Mol. Sci. 2021, 22(5), 2357; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052357 - 26 Feb 2021
Cited by 1 | Viewed by 906
Abstract
Ischemic stroke is a worldwide major cause of mortality and disability and has high costs in terms of health-related quality of life and expectancy as well as of social healthcare resources. In recent years, starting from the bidirectional relationship between autonomic nervous system [...] Read more.
Ischemic stroke is a worldwide major cause of mortality and disability and has high costs in terms of health-related quality of life and expectancy as well as of social healthcare resources. In recent years, starting from the bidirectional relationship between autonomic nervous system (ANS) dysfunction and acute ischemic stroke (AIS), researchers have identified prognostic factors for risk stratification, prognosis of mid-term outcomes and response to recanalization therapy. In particular, the evaluation of the ANS function through the analysis of heart rate variability (HRV) appears to be a promising non-invasive and reliable tool for the management of patients with AIS. Furthermore, preclinical molecular studies on the pathophysiological mechanisms underlying the onset and progression of stroke damage have shown an extensive overlap with the activity of the vagus nerve. Evidence from the application of vagus nerve stimulation (VNS) on animal models of AIS and on patients with chronic ischemic stroke has highlighted the surprising therapeutic possibilities of neuromodulation. Preclinical molecular studies highlighted that the neuroprotective action of VNS results from anti-inflammatory, antioxidant and antiapoptotic mechanisms mediated by α7 nicotinic acetylcholine receptor. Given the proven safety of non-invasive VNS in the subacute phase, the ease of its use and its possible beneficial effect in hemorrhagic stroke as well, human studies with transcutaneous VNS should be less challenging than protocols that involve invasive VNS and could be the proof of concept that neuromodulation represents the very first therapeutic approach in the ultra-early management of stroke. Full article
(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)
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Review
Molecular Biology of Atherosclerotic Ischemic Strokes
Int. J. Mol. Sci. 2020, 21(24), 9372; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249372 - 09 Dec 2020
Cited by 3 | Viewed by 1230
Abstract
Among the causes of global death and disability, ischemic stroke (also known as cerebral ischemia) plays a pivotal role, by determining the highest number of worldwide mortality, behind cardiomyopathies, affecting 30 million people. The etiopathogenetic burden of a cerebrovascular accident could be brain [...] Read more.
Among the causes of global death and disability, ischemic stroke (also known as cerebral ischemia) plays a pivotal role, by determining the highest number of worldwide mortality, behind cardiomyopathies, affecting 30 million people. The etiopathogenetic burden of a cerebrovascular accident could be brain ischemia (~80%) or intracranial hemorrhage (~20%). The most common site when ischemia occurs is the one is perfused by middle cerebral arteries. Worse prognosis and disablement consequent to brain damage occur in elderly patients or affected by neurological impairment, hypertension, dyslipidemia, and diabetes. Since, in the coming years, estimates predict an exponential increase of people who have diabetes, the disease mentioned above constitutes together with stroke a severe social and economic burden. In diabetic patients after an ischemic stroke, an exorbitant activation of inflammatory molecular pathways and ongoing inflammation is responsible for more severe brain injury and impairment, promoting the advancement of ischemic stroke and diabetes. Considering that the ominous prognosis of ischemic brain damage could by partially clarified by way of already known risk factors the auspice would be modifying poor outcome in the post-stroke phase detecting novel biomolecules associated with poor prognosis and targeting them for revolutionary therapeutic strategies. Full article
(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)
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Review
Role of Regular Physical Activity in Neuroprotection against Acute Ischemia
Int. J. Mol. Sci. 2020, 21(23), 9086; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239086 - 29 Nov 2020
Cited by 4 | Viewed by 1001
Abstract
One of the major obstacles that prevents an effective therapeutic intervention against ischemic stroke is the lack of neuroprotective agents able to reduce neuronal damage; this results in frequent evolution towards a long-term disability with limited alternatives available to aid in recovery. Nevertheless, [...] Read more.
One of the major obstacles that prevents an effective therapeutic intervention against ischemic stroke is the lack of neuroprotective agents able to reduce neuronal damage; this results in frequent evolution towards a long-term disability with limited alternatives available to aid in recovery. Nevertheless, various treatment options have shown clinical efficacy. Neurotrophins such as brain-derived neurotrophic factor (BDNF), widely produced throughout the brain, but also in distant tissues such as the muscle, have demonstrated regenerative properties with the potential to restore damaged neural tissue. Neurotrophins play a significant role in both protection and recovery of function following neurological diseases such as ischemic stroke or traumatic brain injury. Unfortunately, the efficacy of exogenous administration of these neurotrophins is limited by rapid degradation with subsequent poor half-life and a lack of blood–brain-barrier permeability. Regular exercise seems to be a therapeutic approach able to induce the activation of several pathways related to the neurotrophins release. Exercise, furthermore, reduces the infarct volume in the ischemic brain and ameliorates motor function in animal models increasing astrocyte proliferation, inducing angiogenesis and reducing neuronal apoptosis and oxidative stress. One of the most critical issues is to identify the relationship between neurotrophins and myokines, newly discovered skeletal muscle-derived factors released during and after exercise able to exert several biological functions. Various myokines (e.g., Insulin-Like Growth Factor 1, Irisin) have recently shown their ability to protects against neuronal injury in cerebral ischemia models, suggesting that these substances may influence the degree of neuronal damage in part via inhibiting inflammatory signaling pathways. The aim of this narrative review is to examine the main experimental data available to date on the neuroprotective and anti-ischemic role of regular exercise, analyzing also the possible role played by neurotrophins and myokines. Full article
(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)
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Review
Genetic Aspects of Inflammation and Immune Response in Stroke
Int. J. Mol. Sci. 2020, 21(19), 7409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197409 - 08 Oct 2020
Cited by 4 | Viewed by 1232
Abstract
Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising [...] Read more.
Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising modes of stroke treatment. One of the important aspects to be considered in the recovery of patients after the stroke is a genetic predisposition, which has been studied extensively. Polymorphisms in a number of candidate genes, such as IL-6, BDNF, COX2, CYPC19, and GPIIIa could be associated with stroke outcome and recovery. Recent GWAS studies pointed to the variant in genesPATJ and LOC as new genetic markers of long term outcome. Epigenetic regulation of immune response in stroke is also important, with mechanisms of histone modifications, DNA methylation, and activity of non-coding RNAs. These complex processes are changing from acute phase over the repair to establishing homeostasis or to provoke exaggerated reaction and death. Pharmacogenetics and pharmacogenomics of stroke cures might also be evaluated in the context of immuno-inflammation and brain plasticity. Potential novel genetic treatment modalities are challenged but still in the early phase of the investigation. Full article
(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)
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Review
Neuroinflammatory Mechanisms in Ischemic Stroke: Focus on Cardioembolic Stroke, Background, and Therapeutic Approaches
Int. J. Mol. Sci. 2020, 21(18), 6454; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186454 - 04 Sep 2020
Cited by 20 | Viewed by 1747
Abstract
One of the most important causes of neurological morbidity and mortality in the world is ischemic stroke. It can be a result of multiple events such as embolism with a cardiac origin, occlusion of small vessels in the brain, and atherosclerosis affecting the [...] Read more.
One of the most important causes of neurological morbidity and mortality in the world is ischemic stroke. It can be a result of multiple events such as embolism with a cardiac origin, occlusion of small vessels in the brain, and atherosclerosis affecting the cerebral circulation. Increasing evidence shows the intricate function played by the immune system in the pathophysiological variations that take place after cerebral ischemic injury. Following the ischemic cerebral harm, we can observe consequent neuroinflammation that causes additional damage provoking the death of the cells; on the other hand, it also plays a beneficial role in stimulating remedial action. Immune mediators are the origin of signals with a proinflammatory position that can boost the cells in the brain and promote the penetration of numerous inflammatory cytotypes (various subtypes of T cells, monocytes/macrophages, neutrophils, and different inflammatory cells) within the area affected by ischemia; this process is responsible for further ischemic damage of the brain. This inflammatory process seems to involve both the cerebral tissue and the whole organism in cardioembolic stroke, the stroke subtype that is associated with more severe brain damage and a consequent worse outcome (more disability, higher mortality). In this review, the authors want to present an overview of the present learning of the mechanisms of inflammation that takes place in the cerebral tissue and the role of the immune system involved in ischemic stroke, focusing on cardioembolic stroke and its potential treatment strategies. Full article
(This article belongs to the Special Issue Immunoinflammatory Background of Neuronal Damage in Stroke)
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