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Molecular Mechanisms of Cerebrovascular Diseases
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Molecular Mechanisms of Cerebrovascular Diseases

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 (28 April 2022) | Viewed by 53572

Special Issue Editors

Prof. Dr. Anuska V. Andjelkovic

E-Mail Website
Guest Editor
1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
2. Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA
Interests: blood brain barrier; stroke; neuroinflammation; vascular malformation; aging; neurodegeneration; cell junctions; epigenetics
Prof. Dr. Richard F. Keep

E-Mail Website
Guest Editor
Department of Neurosurgery, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
Interests: hemorragic stroke; ischemic stroke; blood brain barrier; Blod-CSF barrier neuroinflamamation
Prof. Dr. Michael M. Wang

E-Mail Website
Guest Editor
University of Michigan, Ann Arbor, MI, USA
Interests: CADASIL; vascular dementia; stroke; neuroprotectionnuclear hormone receptor molecular biology

Special Issue Information

Dear colleagues,

Cerebrovascular diseases are a heterogenous group of disorders that affect brain vasculature structure and cerebral blood flow regulation. The common pathological event related to cerebrovascular diseases is stroke, manifested as a sudden cessation of blood flow due to vessel occlusion (ischemic stroke), transient occlusion with recovery (transient ischemic attack), or vessel rupture (hemorrhagic stroke). Brain endothelial cell dysfunction, vessel wall deterioration, and perivascular environment remodeling are major pathological substrates in cerebrovascular diseases. A wide variety of conditions, risk factors, and disorders lead to cerebrovascular diseases, although the underlying molecular mechanisms remain enigmatic. This Special Issue, entitled “Molecular Mechanisms of Cerebrovascular Diseases”, is focused on the molecular mechanisms of endothelial dysfunction and perivascular environment remodeling that lead to lodging of thromboemboli, vessel occlusion and rupture, the mechanism of aging and metabolic vascular wall degeneration, vascular injury and remodeling in sporadic and inherited vascular malformations, and mechanisms of impaired cerebral autoregulation. In addition to “traditional” mechanisms (e.g., inflammation, oxidative stress), this Special Issue welcomes articles that provide an overview of the role of epigenetics, mechanotransduction, and mitochondrial molecular mechanisms in the pathogenesis of cerebrovascular diseases. Studies on the molecular mechanisms associated with cerebral small vessel disease, both sporadic and inherited (i.e., CADASIL and CARASIL), as well as rare disorders, such as MoyaMoya, venous angioma, and Vein of Galen malformation, are also welcome. As such, this Special Issue welcomes submissions of original research and review articles related to any aspect of the molecular mechanisms and pathogenesis of cerebrovascular diseases, identification and exploration of novel targets, and biomarkers.

Prof. Dr. Anuska V. Andjelkovic
Prof. Dr. Richard F. Keep
Prof. Dr. Michael M. Wang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • stroke
  • cerebrovascular malformation
  • small vessel diseases
  • inflammation
  • mitochondria
  • epigenetics
  • biomarkers

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

3 pages, 188 KiB  
Editorial
Molecular Mechanisms of Cerebrovascular Diseases
by Anuska V. Andjelkovic, Richard F. Keep and Michael M. Wang
Int. J. Mol. Sci. 2022, 23(13), 7161; https://doi.org/10.3390/ijms23137161 - 28 Jun 2022
Cited by 1 | Viewed by 1455
Abstract
Cerebrovascular disease involves a range of conditions including ischemic and hemorrhagic stroke, vascular malformations, and vascular cognitive impairment and dementia (VCID) [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)

Research

Jump to: Editorial, Review

15 pages, 2239 KiB  
Article
Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
by Naw May Pearl Cartee, Soo Jung Lee, Kelly Z. Young, Xiaojie Zhang and Michael M. Wang
Int. J. Mol. Sci. 2022, 23(7), 3671; https://doi.org/10.3390/ijms23073671 - 27 Mar 2022
Cited by 4 | Viewed by 1857
Abstract
Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extracellular cysteine number have implicated NOTCH3 cysteine states [...] Read more.
Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extracellular cysteine number have implicated NOTCH3 cysteine states as potential triggers of cerebral vascular smooth muscle cytopathology. In this report, we describe a novel property of the second EGF-like domain of NOTCH3: its capacity to alter the cysteine redox state of the NOTCH3 ectodomain. Synthetic peptides corresponding to this sequence (NOTCH3 N-terminal fragment 2, NTF2) readily reduce NOTCH3 N-terminal ectodomain polypeptides in a dose- and time-dependent fashion. Furthermore, NTF2 preferentially reduces regional domains of NOTCH3 with the highest intensity against EGF-like domains 12–15. This process requires cysteine residues of NTF2 and is also capable of targeting selected extracellular proteins that include TSP2 and CTSH. CADASIL mutations in NOTCH3 increase susceptibility to NTF2-facilitated reduction and to trans-reduction by NOTCH3 produced in cells. Moreover, NTF2 forms complexes with the NOTCH3 ectodomain, and cleaved NOTCH3 co-localizes with the NOTCH3 ectodomain in cerebral arteries of CADASIL patients. The potential for NTF2 to reduce vascular proteins and the enhanced preference for it to trans-reduce mutant NOTCH3 implicate a role for protein trans-reduction in cerebrovascular pathological states such as CADASIL. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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13 pages, 2304 KiB  
Article
Delayed Minocycline Treatment Ameliorates Hydrocephalus Development and Choroid Plexus Inflammation in Spontaneously Hypertensive Rats
by Xiaodi Hao, Fenghui Ye, Katherine G. Holste, Ya Hua, Hugh J. L. Garton, Richard F. Keep and Guohua Xi
Int. J. Mol. Sci. 2022, 23(4), 2306; https://doi.org/10.3390/ijms23042306 - 19 Feb 2022
Cited by 4 | Viewed by 1936
Abstract
Hydrocephalus is a complicated disorder that affects both adult and pediatric populations. The mechanism of hydrocephalus development, especially when there is no mass lesion present causing an obstructive, is poorly understood. Prior studies have demonstrated that spontaneously hypertensive rats (SHRs) develop hydrocephalus by [...] Read more.
Hydrocephalus is a complicated disorder that affects both adult and pediatric populations. The mechanism of hydrocephalus development, especially when there is no mass lesion present causing an obstructive, is poorly understood. Prior studies have demonstrated that spontaneously hypertensive rats (SHRs) develop hydrocephalus by week 7, which was attenuated with minocycline. The aim of this study was to determine sex differences in hydrocephalus development and to examine the effect of minocycline administration after hydrocephalus onset. Male and female Wistar–Kyoto rats (WKYs) and SHRs underwent magnetic resonance imaging at weeks 7 and 9 to determine ventricular volume. Choroid plexus epiplexus cell activation, cognitive deficits, white matter atrophy, and hippocampal neuronal loss were examined at week 9. In the second phase of the experiment, male SHRs (7 weeks old) were treated with either saline or minocycline (20 mg/kg) for 14 days, and similar radiologic, histologic, and behavior tests were performed. Hydrocephalus was present at week 7 and increased at week 9 in both male and female SHRs, which was associated with greater epiplexus cell activation than WKYs. Male SHRs had greater ventricular volume and epiplexus cell activation compared to female SHRs. Minocycline administration improved cognitive function, white matter atrophy, and hippocampal neuronal cell loss. In conclusion, while both male and female SHRs developed hydrocephalus and epiplexus cell activation by week 9, it was more severe in males. Delayed minocycline treatment alleviated hydrocephalus, epiplexus macrophage activation, brain pathology, and cognitive impairment in male SHRs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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12 pages, 2083 KiB  
Article
Differential Role of p53 in Oligodendrocyte Survival in Response to Various Stresses: Experimental Autoimmune Encephalomyelitis, Cuprizone Intoxication or White Matter Stroke
by Fucheng Luo, Zhen Zhang and Yu Luo
Int. J. Mol. Sci. 2021, 22(23), 12811; https://doi.org/10.3390/ijms222312811 - 26 Nov 2021
Cited by 7 | Viewed by 2053
Abstract
Promoting oligodendrocyte viability has been proposed as a therapeutic strategy for alleviating many neuronal diseases, such as multiple sclerosis and stroke. However, molecular pathways critical for oligodendrocyte survival under various stresses are still not well known. p53 is a strong tumor suppressor and [...] Read more.
Promoting oligodendrocyte viability has been proposed as a therapeutic strategy for alleviating many neuronal diseases, such as multiple sclerosis and stroke. However, molecular pathways critical for oligodendrocyte survival under various stresses are still not well known. p53 is a strong tumor suppressor and regulates cell cycle, DNA repair and cell death. Our previous studies have shown that p53 plays an important role in promoting neuronal survival after insults, but its specific role in oligodendrocyte survival is not known. Here, we constructed the mice with oligodendrocyte-specific p53 loss by crossing TRP53flox/flox mice and CNP-cre mice, and found that p53 was dispensable for oligodendrocyte differentiation and myelin formation under physiological condition. In the experimental autoimmune encephalomyelitis (EAE) model, p53 loss of function, specifically in oligodendrocytes, did not affect the EAE disease severity and had no effect on demyelination in the spinal cord of the mice. Interestingly, p53 deficiency in oligodendrocytes significantly attenuated the demyelination of corpus callosum and alleviated the functional impairment of motor coordination and spatial memory in the cuprizone demyelination model. Moreover, the oligodendrocyte-specific loss of p53 provided protection against subcortical white matter damage and mitigated recognition memory impairment in mice in the white matter stroke model. These results suggest that p53 plays different roles in the brain and spinal cord or in response to various stresses. Thus, p53 may be a therapeutic target for oligodendrocyte prevention in specific brain injuries, such as white matter stroke and multiple sclerosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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22 pages, 9227 KiB  
Article
Histone Methyltransferases SUV39H1 and G9a and DNA Methyltransferase DNMT1 in Penumbra Neurons and Astrocytes after Photothrombotic Stroke
by Svetlana Sharifulina, Valentina Dzreyan, Valeria Guzenko and Svetlana Demyanenko
Int. J. Mol. Sci. 2021, 22(22), 12483; https://doi.org/10.3390/ijms222212483 - 19 Nov 2021
Cited by 9 | Viewed by 2289
Abstract
Background: Cerebral ischemia, a common cerebrovascular disease, is one of the great threats to human health and new targets for stroke therapy are needed. The transcriptional activity in the cell is regulated by epigenetic processes such as DNA methylation/demethylation, acetylation/deacetylation, histone methylation, etc. [...] Read more.
Background: Cerebral ischemia, a common cerebrovascular disease, is one of the great threats to human health and new targets for stroke therapy are needed. The transcriptional activity in the cell is regulated by epigenetic processes such as DNA methylation/demethylation, acetylation/deacetylation, histone methylation, etc. Changes in DNA methylation after ischemia can have both neuroprotective and neurotoxic effects depending on the degree of ischemia damage, the time elapsed after injury, and the site of methylation. Methods: In this study, we investigated the changes in the expression and intracellular localization of DNA methyltransferase DNMT1, histone methyltransferases SUV39H1, and G9a in penumbra neurons and astrocytes at 4 and 24 h after stroke in the rat cerebral cortex using photothrombotic stroke (PTS) model. Methods of immunofluorescence microscopy analysis, apoptosis analysis, and immunoblotting were used. Additionally, we have studied the effect of DNMT1 and G9a inhibitors on the volume of PTS-induced infarction and apoptosis of penumbra cells in the cortex of mice after PTS. Results: This study has shown that the level of DNMT1 increased in the nuclear and cytoplasmic fractions of the penumbra tissue at 24 h after PTS. Inhibition of DNMT1 by 5-aza-2′-deoxycytidine protected cells of PTS-induced penumbra from apoptosis. An increase in the level of SUV39H1 in the penumbra was found at 24 h after PTS and G9a was overexpressed at 4 and 24 h after PTS. G9a inhibitors A-366 and BIX01294 protected penumbra cells from apoptosis and reduced the volume of PTS-induced cerebral infarction. Conclusion: Thus, the data obtained show that DNA methyltransferase DNMT1 and histone methyltransferase G9a can be potential protein targets in ischemic penumbra cells, and their inhibitors are potential neuroprotective agents capable of protecting penumbra cells from postischemic damage to the cerebral cortex. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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12 pages, 1958 KiB  
Article
Heparin and Arginine Based Plasmin Nanoformulation for Ischemic Stroke Therapy
by Ramsha Aamir, Cameron Fyffe, Netanel Korin, Daniel A. Lawrence, Enming J. Su and Mathumai Kanapathipillai
Int. J. Mol. Sci. 2021, 22(21), 11477; https://doi.org/10.3390/ijms222111477 - 25 Oct 2021
Cited by 10 | Viewed by 2652
Abstract
Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior [...] Read more.
Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior hemostatic safety profile; however, if injected intravenously it becomes rapidly inactivated by anti-plasmin. Nanoformulations have been shown to increase drug stability and half-life and hence could be applied to increase the plasmin therapeutic efficacy. Here in this paper, we report a novel heparin and arginine-based plasmin nanoformulation that exhibits increased plasmin stability and efficacy. In vitro studies revealed significant plasmin stability in the presence of anti-plasmin and efficient fibrinolytic activity. In addition, these particles showed no significant toxicity or oxidative stress effects in human brain microvascular endothelial cells, and no significant blood brain barrier permeability. Further, in a mouse photothrombotic stroke model, plasmin nanoparticles exhibited significant efficacy in reducing stroke volume without overt intracerebral hemorrhage (ICH) compared to free plasmin treatment. The study shows the potential of a plasmin nanoformulation in ischemic stroke therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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10 pages, 2124 KiB  
Article
Hydrocephalus Following Experimental Subarachnoid Hemorrhage in Rats with Different Aerobic Capacity
by Yasunori Toyota, Hajime Shishido, Fenghui Ye, Lauren G. Koch, Steven L. Britton, Hugh J. L. Garton, Richard F. Keep, Guohua Xi and Ya Hua
Int. J. Mol. Sci. 2021, 22(9), 4489; https://doi.org/10.3390/ijms22094489 - 26 Apr 2021
Cited by 2 | Viewed by 2033
Abstract
Low aerobic capacity is considered to be a risk factor for stroke, while the mechanisms underlying the phenomenon are still unclear. The current study looked into the impacts of different aerobic capacities on early brain injury in a subarachnoid hemorrhage (SAH) model using [...] Read more.
Low aerobic capacity is considered to be a risk factor for stroke, while the mechanisms underlying the phenomenon are still unclear. The current study looked into the impacts of different aerobic capacities on early brain injury in a subarachnoid hemorrhage (SAH) model using rats bred for high and low aerobic capacity (high-capacity runners, HCR; low-capacity runners, LCR). SAH was modeled with endovascular perforation in HCR and LCR rats. Twenty-four hours after SAH, the rats underwent behavioral testing and MRI, and were then euthanized. The brains were used to investigate ventricular wall damage, blood–brain barrier breakdown, oxidative stress, and hemoglobin scavenging. The LCR rats had worse SAH grades (p < 0.01), ventricular dilatation (p < 0.01), ventricular wall damage (p < 0.01), and behavioral scores (p < 0.01). The periventricular expression of HO-1 and CD163 was significantly increased in LCR rats (p < 0.01 each). CD163-positive cells were co-localized with HO-1-positive cells. The LCR rats had greater early brain injuries than HCR rats. The LCR rats had more serious SAH and extensive ventricular wall damage that evolved more frequently into hydrocephalus. This may reflect changes in iron handling and neuroinflammation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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Review

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17 pages, 8983 KiB  
Review
Neuroinflammation in Vascular Cognitive Impairment and Dementia: Current Evidence, Advances, and Prospects
by Zhengming Tian, Xunming Ji and Jia Liu
Int. J. Mol. Sci. 2022, 23(11), 6224; https://doi.org/10.3390/ijms23116224 - 2 Jun 2022
Cited by 44 | Viewed by 4446
Abstract
Vascular cognitive impairment and dementia (VCID) is a major heterogeneous brain disease caused by multiple factors, and it is the second most common type of dementia in the world. It is caused by long-term chronic low perfusion in the whole brain or local [...] Read more.
Vascular cognitive impairment and dementia (VCID) is a major heterogeneous brain disease caused by multiple factors, and it is the second most common type of dementia in the world. It is caused by long-term chronic low perfusion in the whole brain or local brain area, and it eventually develops into severe cognitive dysfunction syndrome. Because of the disease’s ambiguous classification and diagnostic criteria, there is no clear treatment strategy for VCID, and the association between cerebrovascular pathology and cognitive impairment is controversial. Neuroinflammation is an immunological cascade reaction mediated by glial cells in the central nervous system where innate immunity resides. Inflammatory reactions could be triggered by various damaging events, including hypoxia, ischemia, and infection. Long-term chronic hypoperfusion-induced ischemia and hypoxia can overactivate neuroinflammation, causing apoptosis, blood–brain barrier damage and other pathological changes, triggering or aggravating the occurrence and development of VCID. In this review, we will explore the mechanisms of neuroinflammation induced by ischemia and hypoxia caused by chronic hypoperfusion and emphasize the important role of neuroinflammation in the development of VCID from the perspective of immune cells, immune mediators and immune signaling pathways, so as to provide valuable ideas for the prevention and treatment of the disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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16 pages, 1151 KiB  
Review
Shared Inflammatory Pathology of Stroke and COVID-19
by Kathryn E. Sánchez and Gary A. Rosenberg
Int. J. Mol. Sci. 2022, 23(9), 5150; https://doi.org/10.3390/ijms23095150 - 5 May 2022
Cited by 7 | Viewed by 3429
Abstract
Though COVID-19 is primarily characterized by symptoms in the periphery, it can also affect the central nervous system (CNS). This has been established by the association between stroke and COVID-19. However, the molecular mechanisms that cause stroke related to a COVID-19 infection have [...] Read more.
Though COVID-19 is primarily characterized by symptoms in the periphery, it can also affect the central nervous system (CNS). This has been established by the association between stroke and COVID-19. However, the molecular mechanisms that cause stroke related to a COVID-19 infection have not been fully explored. More specifically, stroke and COVID-19 exhibit an overlap of molecular mechanisms. These similarities provide a way to better understand COVID-19 related stroke. We propose here that peripheral macrophages upregulate inflammatory proteins such as matrix metalloproteinases (MMPs) in response to SARS-CoV-2 infection. These inflammatory molecules and the SARS-CoV-2 virus have multiple negative effects related to endothelial dysfunction that results in the disruption of the blood–brain barrier (BBB). Finally, we discuss how the endothelial blood–brain barrier injury alters central nervous system function by leading to astrocyte dysfunction and inflammasome activation. Our goal is to elucidate such inflammatory pathways, which could provide insight into therapies to combat the negative neurological effects of COVID-19. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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16 pages, 946 KiB  
Review
Cerebral Cavernous Malformation Pathogenesis: Investigating Lesion Formation and Progression with Animal Models
by Chelsea M. Phillips, Svetlana M. Stamatovic, Richard F. Keep and Anuska V. Andjelkovic
Int. J. Mol. Sci. 2022, 23(9), 5000; https://doi.org/10.3390/ijms23095000 - 30 Apr 2022
Cited by 4 | Viewed by 3001
Abstract
Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions [...] Read more.
Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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31 pages, 1369 KiB  
Review
Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke
by Kelsy L. Nilles, Erica I. Williams, Robert D. Betterton, Thomas P. Davis and Patrick T. Ronaldson
Int. J. Mol. Sci. 2022, 23(3), 1898; https://doi.org/10.3390/ijms23031898 - 8 Feb 2022
Cited by 25 | Viewed by 4172
Abstract
Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; [...] Read more.
Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood–brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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47 pages, 3795 KiB  
Review
Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke
by Yun Hwa Choi, Collin Laaker, Martin Hsu, Peter Cismaru, Matyas Sandor and Zsuzsanna Fabry
Int. J. Mol. Sci. 2021, 22(17), 9486; https://doi.org/10.3390/ijms22179486 - 31 Aug 2021
Cited by 28 | Viewed by 7150
Abstract
Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via [...] Read more.
Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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24 pages, 9331 KiB  
Review
Role of GPR39 in Neurovascular Homeostasis and Disease
by Yifan Xu, Anthony P. Barnes and Nabil J. Alkayed
Int. J. Mol. Sci. 2021, 22(15), 8200; https://doi.org/10.3390/ijms22158200 - 30 Jul 2021
Cited by 13 | Viewed by 3232
Abstract
GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We [...] Read more.
GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We review GPR39 structure, function, and signaling, including constitutive activity and biased signaling, and summarize its expression pattern in the central nervous system. We further discuss its recognized role in neurovascular, neurological, and neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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16 pages, 1541 KiB  
Review
The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses
by Svetlana Demyanenko and Svetlana Sharifulina
Int. J. Mol. Sci. 2021, 22(15), 7947; https://doi.org/10.3390/ijms22157947 - 26 Jul 2021
Cited by 14 | Viewed by 3515
Abstract
Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and [...] Read more.
Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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23 pages, 6050 KiB  
Review
Neural Stem Cells for Early Ischemic Stroke
by Milton H. Hamblin and Jean-Pyo Lee
Int. J. Mol. Sci. 2021, 22(14), 7703; https://doi.org/10.3390/ijms22147703 - 19 Jul 2021
Cited by 26 | Viewed by 5359
Abstract
Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially [...] Read more.
Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA’s thrombolytic role within the vasculature is beneficial, tPA’s non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA’s detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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Review
Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?
by Nikola Tułowiecka, Dariusz Kotlęga, Andrzej Bohatyrewicz and Małgorzata Szczuko
Int. J. Mol. Sci. 2021, 22(8), 4207; https://doi.org/10.3390/ijms22084207 - 19 Apr 2021
Cited by 12 | Viewed by 3495
Abstract
Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are [...] Read more.
Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cerebrovascular Diseases)
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