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Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway

Inflammopharmacology Aims and scope Submit manuscript

Abstract

Background

Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity.

Hypothesis

Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity.

Study design

This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation.

Methods

Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3 weeks; Group 2 (CFZ/toxic group) received CFZ [4 mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3 weeks; Group 3 (standard treatment group) was administered CFZ (4 mg/kg, i.p.) and olmesartan (2 mg/kg, p.o.) for 3 weeks; Group 4 was administered CFZ (4 mg/kg, i.p.) and rutin (10 mg/kg, p.o.) for 3 weeks; Group 5 was administered CFZ (4 mg/kg, i.p.) and rutin (20 mg/kg, p.o.) for 3 weeks; and Group 6 was administered CFZ (4 mg/kg, i.p.) and rutin (40 mg/kg, p.o.) for 3 weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration.

Results

Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity.

Conclusion

These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.

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Abbreviations

ANOVA:

Analysis of variance

BUN:

Blood urea nitrogen

CAT:

Catalase

CFZ:

Carfilzomib

FDA:

Food and Drug Application

GFR:

Glomerular filtration rate

GR:

Glutathione reductase

GSH:

Reduced glutathione

H&E:

Hematoxylin and eosin

Hb:

Hemoglobin

HTC:

Hematocrit

i.p.:

Intraperitoneal

IkB-α:

Inhibitory kappa-B alpha

IL:

Interleukin

AMDA:

Malondialdehyde

NADPH:

Nicotinamide adenine dinucleotide phosphate

NC:

Normal control

NF-κB:

Nuclear factor kappa-B

NOS:

Nitric oxide synthase

p.o.:

Per oral

RBC:

Red blood cells

RhoA:

Ras homolog gene family, member A

ROCK:

Rho-associated kinase (rho-kinase)

SEM:

Standard error of mean

TBA:

Thiobarbituric acid

TGF-β:

Transforming growth factors

WBC:

White blood cells

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Acknowledgements

The present work was funded by King Saud University, Deanship of Scientific Research, College of Pharmacy (project no. RGP-VPP-305). The authors would like to thank the Department of Pharmacology and Toxicology at the College of Pharmacy, King Saud University for granting us permission to use its facilities.

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Correspondence to Faisal Imam.

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Al-Harbi, N.O., Imam, F., Al-Harbi, M.M. et al. Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway. Inflammopharmacol 27, 817–827 (2019). https://doi.org/10.1007/s10787-018-0550-5

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