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

  • Naif O. Al-Harbi
  • Faisal Imam
  • Mohammed M. Al-Harbi
  • Othman A. Al-Shabanah
  • Moureq Rashed Alotaibi
  • Homood M. As Sobeai
  • Muhammad Afzal
  • Imran Kazmi
  • Ammar Cherkess Al Rikabi
Original Article
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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.

Keywords

Rutin Carfilzomib Nephrotoxicity NOS-2 NF-κB Histopathology 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Naif O. Al-Harbi
    • 1
  • Faisal Imam
    • 1
  • Mohammed M. Al-Harbi
    • 1
  • Othman A. Al-Shabanah
    • 1
  • Moureq Rashed Alotaibi
    • 1
  • Homood M. As Sobeai
    • 1
  • Muhammad Afzal
    • 2
  • Imran Kazmi
    • 3
  • Ammar Cherkess Al Rikabi
    • 4
  1. 1.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhKingdom of Saudi Arabia
  2. 2.Department of Pharmacology and Toxicology, College of PharmacyAl Jauf UniversitySakakahKingdom of Saudi Arabia
  3. 3.Department of Pharmacology and Toxicology, School of PharmacyGlocal UniversitySaharan PurIndia
  4. 4.Department of Pathology, College of MedicineKing Khalid University HospitalRiyadhKingdom of Saudi Arabia

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