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Molecular Pharmacology and Pathology of Strokes

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

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 44937

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Prof. Dr. Joen-Rong Sheu

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Guest Editor

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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
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Prof. Dr. Howard Prentice

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Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
Interests: stroke; Alzheimer’s disease; gene therapy; neuroprotection; neurogenesis
Special Issues, Collections and Topics in MDPI journals

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
Prof. Dr. Howard Prentice
Guest Editors

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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 (10 papers)

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Editorial

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4 pages, 151 KiB

Open AccessEditorial

Molecular Pharmacology and Pathology of Strokes

by Joen-Rong Sheu

Int. J. Mol. Sci. 2018, 19(12), 4103; https://doi.org/10.3390/ijms19124103 - 18 Dec 2018

Viewed by 2855

Abstract

Stroke, an important neurological disease, is becoming an increasingly non-communicable ailment and is the second leading cause of death after coronary heart disease in developed countries [...] Full article

(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)

Research

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18 pages, 4284 KiB

Open AccessArticle

Structure–Activity Relationship Study of Newly Synthesized Iridium-III Complexes as Potential Series for Treating Thrombotic Diseases

by Chih-Hao Yang, Chih-Wei Hsia, Thanasekaran Jayakumar, Joen-Rong Sheu, Chih-Hsuan Hsia, Themmila Khamrang, Yen-Jen Chen, Manjunath Manubolu and Yi Chang

Int. J. Mol. Sci. 2018, 19(11), 3641; https://doi.org/10.3390/ijms19113641 - 19 Nov 2018

Cited by 3 | Viewed by 2870

Abstract

Platelets play a major role in hemostatic events and are associated with various pathological events, such as arterial thrombosis and atherosclerosis. Iridium (Ir) compounds are potential alternatives to platinum compounds, since they exert promising anticancer effects without cellular toxicity. Our recent studies found that Ir compounds show potent antiplatelet properties. In this study, we evaluated the in vitro antiplatelet, in vivo antithrombotic and structure–activity relationship (SAR) of newly synthesized Ir complexes, Ir-1, Ir-2 and Ir-4, in agonists-induced human platelets. Among the tested compounds, Ir-1 was active in inhibiting platelet aggregation induced by collagen; however, Ir-2 and Ir-4 had no effects even at their maximum concentrations of 50 μM against collagen and 500 μM against U46619-induced aggregation. Similarly, Ir-1 was potently inhibiting of adenosine triphosphate (ATP) release, calcium mobilization ([Ca²⁺]i) and P-selectin expression induced by collagen-induced without cytotoxicity. Likewise, Ir-1 expressively suppressed collagen-induced Akt, PKC, p38MAPKs and JNK phosphorylation. Interestingly, Ir-2 and Ir-4 had no effect on platelet function analyzer (PFA-100) collagen-adenosine diphosphate (C-ADP) and collagen-epinephrine (C-EPI) induced closure times in mice, but Ir-1 caused a significant increase when using C-ADP stimulation. Other in vivo studies revealed that Ir-1 significantly prolonged the platelet plug formation, increased tail bleeding times and reduced the mortality of adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism in mice. Ir-1 has no substitution on its phenyl group, a water molecule (like cisplatin) can replace its chloride ion and, hence, the rate of hydrolysis might be tuned by the substituent on the ligand system. These features might have played a role for the observed effects of Ir-1. These results indicate that Ir-1 may be a lead compound to design new antiplatelet drugs for the treatment of thromboembolic diseases. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)

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11 pages, 1425 KiB

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Whole Body Vibration Therapy after Ischemia Reduces Brain Damage in Reproductively Senescent Female Rats

by Ami P. Raval, Marc Schatz, Pallab Bhattacharya, Nathan D’Adesky, Tatjana Rundek, W. Dalton Dietrich and Helen M. Bramlett

Int. J. Mol. Sci. 2018, 19(9), 2749; https://doi.org/10.3390/ijms19092749 - 13 Sep 2018

Cited by 29 | Viewed by 4984

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 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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19 pages, 3366 KiB

Open AccessArticle

Effect of Inhibition of DNA Methylation Combined with Task-Specific Training on Chronic Stroke Recovery

by In-Ae Choi, Cheol Soon Lee, Hahn Young Kim, Dong-Hee Choi and Jongmin Lee

Int. J. Mol. Sci. 2018, 19(7), 2019; https://doi.org/10.3390/ijms19072019 - 11 Jul 2018

Cited by 17 | Viewed by 4004

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 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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19 pages, 4188 KiB

Open AccessArticle

Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death

by A Ra Kho, Bo Young Choi, Song Hee Lee, Dae Ki Hong, Sang Hwon Lee, Jeong Hyun Jeong, Kyoung-Ha Park, Hong Ki Song, Hui Chul Choi and Sang Won Suh

Int. J. Mol. Sci. 2018, 19(5), 1420; https://doi.org/10.3390/ijms19051420 - 09 May 2018

Cited by 54 | Viewed by 5342

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, 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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14 pages, 3373 KiB

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Neuroprotective Effects of Platonin, a Therapeutic Immunomodulating Medicine, on Traumatic Brain Injury in Mice after Controlled Cortical Impact

by Ting-Lin Yen, Chao-Chien Chang, Chi-Li Chung, Wen-Chin Ko, Chih-Hao Yang and Cheng-Ying Hsieh

Int. J. Mol. Sci. 2018, 19(4), 1100; https://doi.org/10.3390/ijms19041100 - 06 Apr 2018

Cited by 13 | Viewed by 4702

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 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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719 KiB

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Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients

by Piotr K. Janicki, Ceren Eyileten, Victor Ruiz-Velasco, Khaled Anwar Sedeek, Justyna Pordzik, Anna Czlonkowska, Iwona Kurkowska-Jastrzebska, Shigekazu Sugino, Yuka Imamura-Kawasawa, Dagmara Mirowska-Guzel and Marek Postula

Int. J. Mol. Sci. 2017, 18(12), 2678; https://doi.org/10.3390/ijms18122678 - 11 Dec 2017

Cited by 10 | Viewed by 4810

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%) 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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3924 KiB

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New Therapeutic Agent against Arterial Thrombosis: An Iridium(III)-Derived Organometallic Compound

by Chih-Wei Hsia, Marappan Velusamy, Jeng-Ting Tsao, Chih-Hsuan Hsia, Duen-Suey Chou, Thanasekaran Jayakumar, Lin-Wen Lee, Jiun-Yi Li and Joen-Rong Sheu

Int. J. Mol. Sci. 2017, 18(12), 2616; https://doi.org/10.3390/ijms18122616 - 05 Dec 2017

Cited by 5 | Viewed by 3705

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. 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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5333 KiB

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Licochalcone A Prevents Platelet Activation and Thrombus Formation through the Inhibition of PLCγ2-PKC, Akt, and MAPK Pathways

by Li-Ming Lien, Kuan-Hung Lin, Li-Ting Huang, Mei-Fang Tseng, Hou-Chang Chiu, Ray-Jade Chen and Wan-Jung Lu

Int. J. Mol. Sci. 2017, 18(7), 1500; https://doi.org/10.3390/ijms18071500 - 12 Jul 2017

Cited by 44 | Viewed by 6461

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 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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12 pages, 3185 KiB

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Possible Molecular Targets of Novel Ruthenium Complexes in Antiplatelet Therapy

by Thanasekaran Jayakumar, Chia-Yuan Hsu, Themmila Khamrang, Chih-Hsuan Hsia, Chih-Wei Hsia, Manjunath Manubolu and Joen-Rong Sheu

Int. J. Mol. Sci. 2018, 19(6), 1818; https://doi.org/10.3390/ijms19061818 - 20 Jun 2018

Cited by 12 | Viewed by 4384

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 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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