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Special Issue "Molecular Pharmacology and Pathology of Strokes"

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: 20 November 2018

Special Issue Editors

Guest Editor
Prof. Dr. Joen-Rong Sheu

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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Interests: clinical and translational research; free radicals and oxidative stress; inflammation and microglia; neuroregeneration and neurodegeneration; novel drug development (bioactive and chemical synthesis) for treatment of stroke; pathological mechanisms; platelet activation and arterial thrombosis; hyperlipidemia and vascular diseases
Co-Guest Editor
Dr. Howard Prentice

Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
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Special Issue Information

Dear Colleagues,

Stroke is an acute neurological event leading to neural tissue death in the brain, causing motor, sensory, and cognitive function loss. It is the second leading cause of death after coronary heart disease in developed countries. Despite the major advancements in cerebrovascular medicine over the past 50 years, stroke remains the number one public health concern and primary causes of death today. Breakthroughs in elucidating the basic molecular pharmacology in cerebrovascular function and thrombosis/coagulation, has led to significant advancements in the current treatment paradigm for patients with stroke. Innovation in these areas of research has led to remarkable discoveries and significantly reduced the mortality and morbidity from stroke. Nevertheless, more work and a tenacious pursuit of the basic/clinical sciences in cerebrovascular pathology and pharmacology are still wanted. The purpose of this Special Issue is to present knowledge of prevention and treatment by the use of novel drugs and nutraceuticals, with the help of our co-workers and globally-associated researchers. We encourage contribution by original research articles, as well as review articles, which will motivate the remaining efforts to understand the pathology underlying cerebrovascular diseases, and neurodegenerations, the development of strategies to prevent and treat these conditions, evaluation of outcomes, and epidemiological and clinical studies.

Prof. Dr. Joen-Rong Sheu
Guest Editor

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 papers will be 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 monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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

  • platelet activation and thrombosis
  • vascular diseases
  • novel drug development
  • neuroprotection
  • pathogenic mechanisms
  • free radicals/oxidative stress
  • inflammation
  • signal transductions
  • clinical and translational research

Published Papers (8 papers)

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Research

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Open AccessArticle Whole Body Vibration Therapy after Ischemia Reduces Brain Damage in Reproductively Senescent Female Rats
Int. J. Mol. Sci. 2018, 19(9), 2749; https://doi.org/10.3390/ijms19092749
Received: 23 August 2018 / Revised: 3 September 2018 / Accepted: 5 September 2018 / Published: 13 September 2018
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Abstract
A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several
[...] Read more.
A risk of ischemic stroke increases exponentially after menopause. Even a mild-ischemic stroke can result in increased frailty. Frailty is a state of increased vulnerability to adverse outcomes, which subsequently increases risk of cerebrovascular events and severe cognitive decline, particularly after menopause. Several interventions to reduce frailty and subsequent risk of stroke and cognitive decline have been proposed in laboratory animals and patients. One of them is whole body vibration (WBV). WBV improves cerebral function and cognitive ability that deteriorates with increased frailty. The goal of the current study is to test the efficacy of WBV in reducing post-ischemic stroke frailty and brain damage in reproductively senescent female rats. Reproductively senescent Sprague-Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO) and were randomly assigned to either WBV or no-WBV groups. Animals placed in the WBV group underwent 30 days of WBV (40 Hz) treatment performed twice daily for 15 min each session, 5 days each week. The motor functions of animals belonging to both groups were tested intermittently and at the end of the treatment period. Brains were then harvested for inflammatory markers and histopathological analysis. The results demonstrate a significant reduction in inflammatory markers and infarct volume with significant increases in brain-derived neurotrophic factor and improvement in functional activity after tMCAO in middle-aged female rats that were treated with WBV as compared to the no-WBV group. Our results may facilitate a faster translation of the WBV intervention for improved outcome after stroke, particularly among frail women. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Open AccessArticle Effect of Inhibition of DNA Methylation Combined with Task-Specific Training on Chronic Stroke Recovery
Int. J. Mol. Sci. 2018, 19(7), 2019; https://doi.org/10.3390/ijms19072019
Received: 23 May 2018 / Revised: 7 July 2018 / Accepted: 9 July 2018 / Published: 11 July 2018
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Abstract
To develop new rehabilitation therapies for chronic stroke, this study examined the effectiveness of task-specific training (TST) and TST combined with DNA methyltransferase inhibitor in chronic stroke recovery. Eight weeks after photothrombotic stroke, 5-Aza-2′-deoxycytidine (5-Aza-dC) infusion was done on the contralesional cortex for
[...] Read more.
To develop new rehabilitation therapies for chronic stroke, this study examined the effectiveness of task-specific training (TST) and TST combined with DNA methyltransferase inhibitor in chronic stroke recovery. Eight weeks after photothrombotic stroke, 5-Aza-2′-deoxycytidine (5-Aza-dC) infusion was done on the contralesional cortex for four weeks, with and without TST. Functional recovery was assessed using the staircase test, the cylinder test, and the modified neurological severity score (mNSS). Axonal plasticity and expression of brain-derived neurotrophic factor (BDNF) were determined in the contralateral motor cortex. TST and TST combined with 5-Aza-dC significantly improved the skilled reaching ability in the staircase test and ameliorated mNSS scores and cylinder test performance. TST and TST with 5-Aza-dC significantly increased the crossing fibers from the contralesional red nucleus, reticular formation in medullar oblongata, and dorsolateral spinal cord. Mature BDNF was significantly upregulated by TST and TST combined with 5-Azd-dC. Functional recovery after chronic stroke may involve axonal plasticity and increased mature BDNF by modulating DNA methylation in the contralesional cortex. Our results suggest that combined therapy to enhance axonal plasticity based on TST and 5-Aza-dC constitutes a promising approach for promoting the recovery of function in the chronic stage of stroke. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Open AccessArticle Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death
Int. J. Mol. Sci. 2018, 19(5), 1420; https://doi.org/10.3390/ijms19051420
Received: 11 April 2018 / Revised: 8 May 2018 / Accepted: 8 May 2018 / Published: 9 May 2018
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Abstract
Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood,
[...] Read more.
Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood–brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Open AccessArticle Neuroprotective Effects of Platonin, a Therapeutic Immunomodulating Medicine, on Traumatic Brain Injury in Mice after Controlled Cortical Impact
Int. J. Mol. Sci. 2018, 19(4), 1100; https://doi.org/10.3390/ijms19041100
Received: 31 January 2018 / Revised: 2 April 2018 / Accepted: 3 April 2018 / Published: 6 April 2018
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Abstract
Traumatic brain injury (TBI) is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied
[...] Read more.
Traumatic brain injury (TBI) is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied by neuroinflammation, microglial activation, and additional cell death subsequently occur. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers, and some types of acute inflammation. In the present study, the neuroprotective effects of platonin against TBI were explored in a controlled cortical impact (CCI) injury model in mice. Treatment with platonin (200 µg/kg) significantly reduced the neurological severity score, general locomotor activity, and anxiety-related behavior, and improved the rotarod performance of CCI-injured mice. In addition, platonin reduced lesion volumes, the expression of cleaved caspase-3, and microglial activation in TBI-insulted brains. Platonin also suppressed messenger (m)RNA levels of caspase-3, caspase-1, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β. On the other hand, free radical production after TBI was obviously attenuated in platonin-treated mice. Treatment with platonin exhibited prominent neuroprotective properties against TBI in a CCI mouse model through its anti-inflammatory, anti-apoptotic, and anti-free radical capabilities. This evidence collectively indicates that platonin may be a potential therapeutic medicine for use with TBIs. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Open AccessArticle Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
Int. J. Mol. Sci. 2017, 18(12), 2678; https://doi.org/10.3390/ijms18122678
Received: 20 September 2017 / Revised: 5 December 2017 / Accepted: 7 December 2017 / Published: 11 December 2017
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Abstract
The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%)
[...] Read more.
The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population. The genes selected for re-sequencing consisted of 26 genes coding for proteins associated with the surface membrane of platelets. Targeted pooled re-sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of large-vessel IS) and 500 controls. After quality control and prioritization based on allele frequency and damaging probability, follow-up individual genotyping of deleterious rare variants was performed in patients from the original cohort. Gene-based analyses identified an association between IS and 6 rare functional and damaging variants in the purinergic genes (P2RY1 and P2RY12 locus). The predicted properties of the most damaging rare variants in P2RY1 and P2RY12 were confirmed by using mouse fibroblast cell cultures transfected with plasmid constructs containing cDNA of mutated variants (FLIPR on FlexStation3). This study identified a putative role for rare variants in P2RY1 and P2RY12 genes involved in platelet reactivity on large-vessel IS susceptibility in a Polish population. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Open AccessArticle New Therapeutic Agent against Arterial Thrombosis: An Iridium(III)-Derived Organometallic Compound
Int. J. Mol. Sci. 2017, 18(12), 2616; https://doi.org/10.3390/ijms18122616
Received: 12 October 2017 / Revised: 15 November 2017 / Accepted: 29 November 2017 / Published: 5 December 2017
Cited by 1 | PDF Full-text (3924 KB) | HTML Full-text | XML Full-text
Abstract
Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer.
[...] Read more.
Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir) is considered a potential alternative. We recently developed an Ir(III)-derived complex, [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-11), which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP) release, intracellular Ca2+ mobilization, P-selectin expression, and OH· formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2–PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Open AccessArticle Licochalcone A Prevents Platelet Activation and Thrombus Formation through the Inhibition of PLCγ2-PKC, Akt, and MAPK Pathways
Int. J. Mol. Sci. 2017, 18(7), 1500; https://doi.org/10.3390/ijms18071500
Received: 5 June 2017 / Revised: 7 July 2017 / Accepted: 9 July 2017 / Published: 12 July 2017
Cited by 4 | PDF Full-text (5333 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Platelet activation is involved in cardiovascular diseases, such as atherosclerosis and ischemic stroke. Licochalcone A (LA), an active ingredient of licorice, exhibits multiple biological activities such as anti-oxidation and anti-inflammation. However, its role in platelet activation remains unclear. Therefore, the study investigated the
[...] Read more.
Platelet activation is involved in cardiovascular diseases, such as atherosclerosis and ischemic stroke. Licochalcone A (LA), an active ingredient of licorice, exhibits multiple biological activities such as anti-oxidation and anti-inflammation. However, its role in platelet activation remains unclear. Therefore, the study investigated the antiplatelet mechanism of LA. Our data revealed that LA (2–10 μM) concentration dependently inhibited platelet aggregation induced by collagen, but not thrombin and U46619. LA markedly attenuated collagen-stimulated ATP release, P-selectin secretion, calcium mobilization, and GPIIbIIIa activation, but did not interfere with the collagen binding to platelets. Moreover, LA significantly reduced the activation of PLCγ2, PKC, Akt and MAPKs. Thus, LA attenuates platelet activation, possibly by inhibiting collagen receptor downstream signaling but not by blocking the collagen receptors. In addition, LA prevented adenosine diphosphate (ADP)-induced acute pulmonary thrombosis, fluorescein sodium-induced platelet thrombus formation, and middle cerebral artery occlusion/reperfusion-induced brain injury in mice, but did not affect normal hemostasis. This study demonstrated that LA effectively reduced platelet activation and thrombus formation, in part, through the inhibition of PLCγ2–PKC, Akt, and MAPK pathways, without the side effect of bleeding. These findings also indicate that LA may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders such as stroke. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Review

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Open AccessReview Possible Molecular Targets of Novel Ruthenium Complexes in Antiplatelet Therapy
Int. J. Mol. Sci. 2018, 19(6), 1818; https://doi.org/10.3390/ijms19061818
Received: 1 June 2018 / Revised: 13 June 2018 / Accepted: 15 June 2018 / Published: 20 June 2018
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Abstract
In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is
[...] Read more.
In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is liable for the majority of CVD-related deaths. Platelets, an anuclear and small circulating blood cell, play key roles in hemostasis by inhibiting unnecessary blood loss of vascular damage by making blood clot. Platelet activation also plays a role in cancer metastasis and progression. Nevertheless, abnormal activation of platelets results in thrombosis under pathological settings such as the rupture of atherosclerotic plaques. Thrombosis diminishes the blood supply to the heart and brain resulting in heart attacks and strokes, respectively. While currently used anti-platelet drugs such as aspirin and clopidogrel demonstrate efficacy in many patients, they exert undesirable side effects. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a demanding priority. Recently, precious metal drugs have conquered the subject of metal-based drugs, and several investigators have motivated their attention on the synthesis of various ruthenium (Ru) complexes due to their prospective therapeutic values. Similarly, our recent studies established that novel ruthenium-based compounds suppressed platelet aggregation via inhibiting several signaling cascades. Our study also described the structure antiplatelet-activity relationship (SAR) of three newly synthesized ruthenium-based compounds. This review summarizes the antiplatelet activity of newly synthesized ruthenium-based compounds with their potential molecular mechanisms. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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