Honokiol as a specific collagen receptor glycoprotein VI antagonist on human platelets: Functional ex vivo and in vivo studies

The existence of mitogen activated protein kinases (MAPKs) in platelets has been known for more than 20 years. Since that time hundreds of reports have been published describing the conditions that cause MAPK activation in platelets and their role in regulating diverse platelet functions from the molecular to physiological level. However, this cacophony of reports, with inconsistent and sometimes contradictory findings, has muddied the waters leading to great confusion. Since the last review of platelet MAPKs was published more than a decade ago, there have been more than 50 reports, including the description of novel knockout mouse models, that have furthered our knowledge. Therefore, we undertook an extensive literature review to delineate what is known about platelet MAPKs. We specifically discuss what is currently known about how MAPKs are activated and what signaling cascades they regulate in platelets incorporating recent findings from knockout mouse models. In addition, we will discuss the role each MAPK plays in regulating distinct platelet functions. In doing so, we hope to clarify the role for MAPKs and identify knowledge gaps in this field that await future researchers. In addition, we discuss the limitations of current studies with a particular focus on the off‐target effects of commonly used MAPK inhibitors. We conclude with a look at the clinical utility of MAPK inhibitors as potential antithrombotic therapies with an analysis of current clinical trial data.

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“…While these receptors can be quite different in both function and signaling, all major platelet receptors can activate MAPKs (Figure 2). 14‐24 …”

Section: Mapk Activation In Plateletsmentioning

confidence: 99%

Platelet MAPKs—a 20+ year history: What do we really know?

Patel

Naik

2020

Journal of Thrombosis and Haemostasis

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“…Honokiol has emerged as a multifunctional compound with many potential therapeutic properties (Fig. ), including antioxidant, anti‐inflammatory, antimicrobial, anticancer, antithrombotic, antidepressant, and neuroprotective activities . Honokiol has been reported to cross the blood brain barrier suggesting that can be a powerful therapeutic compound against a broad spectrum of neurological disorders .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of honokiol: from chemistry to medicine

et al. 2017

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The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities. Honokiol can permeate the blood brain barrier and the blood-cerebrospinal fluid to increase its bioavailability in neurological tissues. Diverse studies have provided evidence on the neuroprotective effect of honokiol in the central nervous system, due to its potent antioxidant activity, and amelioration of the excitotoxicity mainly related to the blockade of glutamate receptors and reduction in neuroinflammation. In addition, recent studies suggest that honokiol can attenuate neurotoxicity exerted by abnormally aggregated Aβ in Alzheimer's disease. The present work summarizes what is currently known concerning the neuroprotective effects of honokiol and its potential molecular mechanisms of action, which make it considered as a promising agent in the treatment and management of neurodegenerative diseases. © 2017 BioFactors, 43(6):760-769, 2017.

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“…Similarly, caffeic acid phenethyl ester (CAPE) [11], its analogue CAPE-NO 2 [12], Honokiol and Hinokitiol [13][14][15] are bioactive compounds derived from plant or other natural sources known to inhibit collagen-induced platelet activation. Recently, a synthetic platelet GPVI antagonist, S002-333 belonging to a new class of 2,3-disubstituted tetrahydropyridoindoles showed promising antithrombotic efficacy in animal and in vitro models [16].…”

Section: Introductionmentioning

confidence: 99%

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

Misra

Prakash

Aggarwal

et al. 2018

Biochemical Pharmacology

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Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2-fold) and maintained a sustained blood flow velocity for >30 min. Comparatively, clopidogrel showed significant prolongation in TTO (1.3-fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained hemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7-fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300 µM), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV (53.4 ± 5.7%). Mechanistically, S007-867 (10-300 μM) inhibited collagen-induced ATP release, thromboxane A (TxA) generation, intra-platelet [Ca] flux and global tyrosine phosphorylation including PLCγ2. Collectively the present study highlights that S007-867 is a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, S007-867 may be further developed for the treatment of thrombotic disorders in clinical settings.

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Honokiol as a specific collagen receptor glycoprotein VI antagonist on human platelets: Functional ex vivo and in vivo studies

Cited by 23 publications

References 45 publications

Platelet MAPKs—a 20+ year history: What do we really know?

Platelet MAPKs—a 20+ year history: What do we really know?

Neuroprotective effects of honokiol: from chemistry to medicine

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

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