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Hepatoprotective effect of limonin, a natural limonoid from the seed of Citrus aurantium var. bigaradia, on D-galactosamine-induced liver injury in rats

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Abstract

Toll-like receptors have been implicated in inflammation and injury in various tissues and organs including the liver. We have investigated the effects of limonin isolated from the dichloromethane fraction of the seeds of bittersweet orange (Citrus aurantium var. bigaradia) in two dose levels (50 and 100 mg/kg) against D-galactosamine (D-GalN)-induced liver toxicity in comparison with standard silymarin treatment on Toll-like receptors expression and hepatic injury, using a well-established rat model of acute hepatic inflammation. The limonoids in the seeds of bittersweet orange were identified. Oral administration of limonin before D-GalN injection, significantly attenuated markers of hepatic damage (elevated liver enzyme activities and total bilirubin) and hepatic inflammation (TNF-α, infiltration of neutrophils), oxidative stress and expression of TLR-4 but not TLR-2 in D-GalN-treated rats. Limonin effects were similar in most aspects to that of the lignan silymarin. The higher dose of limonin (100 mg/kg) performed numerically better for AST and bilirubin, and both doses yielded similar results for ALT and GGT. While the lower dose of limonin (50 mg/kg) performed better against oxidative stress and liver structural damage as compared to the higher dose. Limonin exerts protective effects on liver toxicity associated with inflammation and tissue injury via attenuation of inflammation and reduction of oxidative stress.

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Acknowledgments

This work was funded by Zagazig University, project 5K2/M4 (to AE). The authors would like to thank Prof. L. Rashed (Biochemistry Department, Faculty of Medicine, Cairo University, Egypt) for assistance in performing PCR technique. Dr. A. Ahmed, Faculty of Veterinary Medicine, Zagazig University for histopathological examination of liver and A. Tahrani, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Germany for running LC-MS.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    Mona F. Mahmoud

  2. Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    Dalia I. Hamdan & Assem M. El-Shazly

  3. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany

    Michael Wink

  4. Department of Pharmacology, Faculty of Pharmacy, University of Zagazig, Zagazig, 44519, Egypt

    Mona F. Mahmoud

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  1. Mona F. Mahmoud
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  2. Dalia I. Hamdan
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Correspondence to Mona F. Mahmoud.

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Mahmoud, M.F., Hamdan, D.I., Wink, M. et al. Hepatoprotective effect of limonin, a natural limonoid from the seed of Citrus aurantium var. bigaradia, on D-galactosamine-induced liver injury in rats. Naunyn-Schmiedeberg's Arch Pharmacol 387, 251–261 (2014). https://doi.org/10.1007/s00210-013-0937-1

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