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Enoxaparin prevents fibrin accumulation in liver tissues and attenuates methotrexate-induced liver injury in rats

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A Correction to this article was published on 29 April 2020

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Abstract

Methotrexate (MTX) is a widely used drug for treatment of many malignant, rheumatic, and autoimmune diseases. However, hepatotoxicity remains one of the most serious side effects of MTX. The extrinsic coagulation pathway is activated after tissue injury through the release of tissue factor (TF) which activates a cascade of clotting factors including prothrombin and fibrinogen. Liver sinusoidal endothelial cells express endothelial nitric oxide synthase (eNOS) as a source for nitric oxide (NO) that serves as vasodilator and antithrombotic factor. In the current study, we tested the possible role of coagulation system activation in MTX-induced hepatotoxicity. Our results showed that single-dose administration of MTX significantly altered rat liver functions with concurrent turbulence in redox status. Immunofluorescence staining showed accumulation of fibrin in the periportal hepatocytes and downregulation of eNOS expression in hepatic endothelial and sinusoidal cells following MTX treatment. Moreover, MTX administration increased the expression of inducible nitric oxide synthase (iNOS) and NOSTRIN (eNOS traffic inducer) in the hepatic sinusoids. On the other hand, pre-treatment with enoxaparin rescued against MTX-induced liver injury with subsequent amelioration of liver redox status. Furthermore, it significantly prevented the effect of MTX on the expression of fibrin, iNOS, eNOS, and NOSTRIN. We concluded that liver tissue aggregation of the coagulation product, fibrin, may play a crucial role in the pathogenesis of MTX-induced liver injury.

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  • 29 April 2020

    The authors found a mistake in Figure 2 and would like to correct the manuscript.

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Authors and Affiliations

  1. Faculty of pharmacy, Al-Azhar University, Cairo, Egypt

    Mohamed G. Ewees, Tamer M. Abdelghany, Abdel-Aziz H. Abdel-Aziz & Mohamed S. Abdelbakky

  2. Faculty of pharmacy, Nahda University, Beni-Suef, Egypt

    Mohamed S. Abdelbakky

Authors
  1. Mohamed G. Ewees
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  2. Tamer M. Abdelghany
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  3. Abdel-Aziz H. Abdel-Aziz
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  4. Mohamed S. Abdelbakky
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Correspondence to Mohamed G. Ewees.

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All animal procedures were approved by the ethical committee in Al-Azhar University and performed in accordance with the regulations of the international guide for the care and use of laboratory animals.

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The authors declare that there is no conflict of interest.

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Ewees, M.G., Abdelghany, T.M., Abdel-Aziz, AA.H. et al. Enoxaparin prevents fibrin accumulation in liver tissues and attenuates methotrexate-induced liver injury in rats. Naunyn-Schmiedeberg's Arch Pharmacol 392, 623–631 (2019). https://doi.org/10.1007/s00210-019-01618-1

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