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Protective effects of melatonin and l-carnitine against methotrexate-induced toxicity in isolated rat hepatocytes

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Abstract

The present study was designed to evaluate the possible protective effects of melatonin (MEL) and/or l-carnitine (L-CAR) against methotrexate (MTX)-induced toxicity in isolated rat hepatocytes. Hepatocytes were prepared using collagenase techniques of perfusion and digestion of rat liver. Trypan blue uptake, as well as, glutathione (GSH), lipid peroxidation (LPO), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α) levels were measured. Caspase-3 activity was also assessed. Pre-incubation of hepatocytes with MEL (1 mM) and/or l-CAR (10 mM) 30 min prior to intoxication with MTX, significantly protected hepatocytes against toxicity. In addition, LPO, NO, TNF-α levels, and caspase-3 activity were decreased in comparison to the MTX-intoxicated group. Furthermore, the two drugs increased the MTX-depleted GSH level. MEL and L-CAR prevented MTX-induced hepatocytotoxicity, at least partly, by their antioxidative, antiinflammatory, and antiapoptotic effects. Further studies are recommended on the clinical pharmacologic and toxicologic effects of MEL and L-CAR in patients receiving MTX.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

Ac-DEVD-pNA:

Acetyl-Asp-Glu-Val-Asp p-nitroanilide

AFMK:

N1-acetyl-N2-formyl-5-methoxykynuramine

AMK N1:

Acetyl-5-methoxykynuramine

ANOVA:

Analysis of variance

Apaf-1:

Apoptotic protease activating factor-1

BSA:

Bovine serum albumin

DHFR:

Dihydrofolate reductase

DMSO:

Dimethyl sulfoxide

DMEM:

Dulbecco’s modified Eagle medium

EDTA:

Ethylenediaminetetraacetic acid

ETC:

Electron transport chain

FBS:

Fetal bovine serum

GSH:

Reduced glutathione

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

iNOS:

Inducible nitric oxide synthase

IL-6:

Interleukin-6

IL-1β:

Interleukin-1β

KH:

Krebs-Henseleit

L-CAR:

L-Carnitine

LP:

Lipid peroxidation

MDA:

Malondialdehyde

MEL:

Melatonin

MTX:

Methotrexate

NADPH:

Nicotinamide adenine dinucleotide phosphate

NED:

Naphylethylenediaminedihydrochloride

NF-κB:

Nuclear factor kappa B

Nrf2:

Nuclear factor erythroid 2–related factor 2

NO:

Nitric oxide

Opm:

Oscillations per minute

PBS:

Phosphate-buffered saline

pNA p:

Nitroaniline

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SNA:

Sulfanilamide

TMP:

Tetramethoxypropane

TB:

Trypan blue

TNF-α:

Tumor necrosis factor-alpha

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Authors and Affiliations

  1. Pharmacology & Toxicology Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt

    Lamiaa A. Khatab, Ihab T. Abdel-Raheem & Asser I. Ghoneim

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  1. Lamiaa A. Khatab
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  2. Ihab T. Abdel-Raheem
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  3. Asser I. Ghoneim
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Contributions

A.I.G., I.T.A., and L.A.K. conceived and designed research. L.A.K. and A.I.G. conducted experiments. L.A.K. and A.I.G. contributed materials, technical, and analytical tools. L.A.K., I.T.A., and A.I.G. analyzed data. A.I.G., I.T.A., and L.A.K. wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Lamiaa A. Khatab.

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Khatab, L.A., Abdel-Raheem, I.T. & Ghoneim, A.I. Protective effects of melatonin and l-carnitine against methotrexate-induced toxicity in isolated rat hepatocytes. Naunyn-Schmiedeberg's Arch Pharmacol 395, 87–97 (2022). https://doi.org/10.1007/s00210-021-02176-1

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