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The potential curative effect of rebamipide in hepatic ischemia/reperfusion injury

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Abstract

Rebamipide (Reba), a gastroprotective drug, has signified its hepatoprotective activity; however, its possible post-therapeutic intervention in hepatic ischemia/reperfusion (I/R) remains elusive. Consequently, the intent of this study was to test Reba modulatory effect on nuclear factor (NF)-κB signaling in hepatic I/R model. Rats were randomized into sham, I/R, Reba 60, and Reba100 (60 and 100 mg/kg, respectively) groups. Ischemia was induced for 30 min followed by 3-day reperfusion to set up a model of partial (70%) warm hepatic ischemia. Post-treatment with Reba reduced the serum level of alanine transaminase, improved histopathological alterations of the liver, and elevated hepatic adenosine triphosphate. It also lowered hepatic lipid peroxides and increased both total antioxidant capacity and nitric oxide. Besides, Reba decreased tumor necrosis factor-α, interferon-γ, intercellular adhesion molecule-1, myeloperoxidase, prostaglandin E2, cyclooxygenase-2 expression/content, and caspase-3 activity. Reba also upregulated the gene expression/content of sirtuin 1 (SIRT-1), while it downregulated that of high mobility group box (HMGB)1 and reduced the expression/content of NF-κB p65/pS536-NF-κB and the content of pT180/Y182-p38MAPK. Reba provided tenable hepato-therapeutic mechanisms to mitigate events concomitant with hepatic I/R via inhibition of NF-κB p65 and modulation of its influential signals (SIRT-1, HMGB1, p38MAPK) associated with its antiinflammatory, antioxidant, and antiapoptotic impacts.

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Abbreviations

ALT:

Alanine transaminase

ANOVA:

Analysis of variance

ATP:

Adenosine triphosphate

COX-2:

Cyclooxygenase-2

GAPDH:

Glyceraldehyde-3 phosphate dehydrogenase

H&E:

Hematoxylin and eosin

HMGB1:

High mobility group box 1

I/R:

Ischemia/reperfusion

ICAM-1:

Intercellular adhesion molecule-1

IFN-γ:

Interferon-gamma

MDA:

Malondialdehyde

MPO:

Myeloperoxidase

NAD+ :

Nicotinamide adenine dinucleotide

NF-κB p65:

Nuclear factor-kappa B p65

NIH:

National Institutes of Health

NOx:

Total nitric oxide

p38 MAPK:

p38 mitogen-activated protein kinase

PGE2 :

Prostaglandin E2

qPCR:

Quantitative real-time polymerase chain reaction

Reba:

Rebamipide

ROS:

Reactive oxygen species

SEM:

Standard error of mean

SIRT-1:

Sirtuin 1

TAC:

Total antioxidant capacity

TNF-α:

Tumor necrosis factor-alpha

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Acknowledgements

The authors would like to thank Prof. Dr. A. Bakear (Pathology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt) for his assistance in the histopathological examination.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty Pharmacy, October 6 University, Giza, 12585, Egypt

    Abdallah M. Gendy

  2. Department of Pharmacology and Toxicology, Faculty Pharmacy, Cairo University, Kasr El-Aini Str, Cairo, 11562, Egypt

    Dalaal M. Abdallah & Hanan S. El-Abhar

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  1. Abdallah M. Gendy
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  2. Dalaal M. Abdallah
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  3. Hanan S. El-Abhar
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Contributions

A.M.G., D.M.A., and H.S.E. conceived and designed the experiments, wrote the manuscript, and approved the final submission. A.M.G. performed the experiments and analyzed the data. H.S.E. and D.M.A. lead the research.

Corresponding author

Correspondence to Dalaal M. Abdallah.

Ethics declarations

The study was approved by the Research Ethics Committee (Faculty of Pharmacy, Cairo University, Cairo, Egypt; PT 1302) and complies with the published Guide for Care and Use of Laboratory Animals No. 8023 (NIH Publications, USA, 1978).

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The authors declare that they have no conflict of interest.

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Gendy, A.M., Abdallah, D.M. & El-Abhar, H.S. The potential curative effect of rebamipide in hepatic ischemia/reperfusion injury. Naunyn-Schmiedeberg's Arch Pharmacol 390, 691–700 (2017). https://doi.org/10.1007/s00210-017-1370-7

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