Elsevier

Toxicology Reports

Volume 5, 2018, Pages 687-694
Toxicology Reports

Immunosuppressant drug tacrolimus induced mitochondrial nephrotoxicity, modified PCNA and Bcl-2 expression attenuated by Ocimum basilicum L. in CD1 mice

https://doi.org/10.1016/j.toxrep.2018.06.003Get rights and content
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Highlights

  • Tacrolimus (TAC), an immunosuppressant drug has been demonstrated to augment free radical production.

  • It increased serum creatinine, BUN and oxidative deterioration of cellular tissues in CD-1 mice.

  • TAC-induced nephrotoxicity altered the mitochondrial antioxidant defense, expression of PCNA, Bcl2.

  • TAC-induced changes are ameliorated by pretreatment of Ocimum basilicum L (OB).

  • OB can be considered as a potential source of antioxidants, phenols, alkaloids with potent nephroprotective activity.

Abstract

Tacrolimus (TAC) is used sporadically as an immunosuppressive agent for organ transplantation, but its clinical used is limited due to its marked nephrotoxicity. Ocimum basilicum L. (Lamiaceae) (OB) had been shown to possess antioxidant, anti-inflammatory and nephroprotective activity, and effective at improving renal inflammation and glomerular. In our study, we aim to evaluate the efficacy of the OB against TAC-induced mitochondrial nephrotoxicity in CD1 mice. Mice were randomly divided into four groups. Group 1 (control group); administered orally with normal saline (1 mL/kg) for two weeks; Group 2 (OB extract treated-group) (500 mg/kg b.wt) gavaged once/day for two weeks; Group 3 (TAC-treated group) (3 mg/kg b.wt, administered ip once a day for two weeks); and Group 4; (TAC plus OB extract treated-group). Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. The OB extract was high in phenolic content (50.3 mg/g of gallic acid equivalent), total flavonoids (14.5 mg/g CE equivalent). The potential antioxidant efficacy of the extract (IC50) was 24.5 μg/mL. OB pretreatment significantly improved the TAC-induced changes in biochemical markers of nephrotoxicity for instance blood urea nitrogen (BUN), creatinine, total protein, and albumin (P < 0.01, when compared with TAC treated group). Also, it significantly restored the increase activities of TBARS, protein carbonyl (PC) (P < 0.001, when compared to healthy control group) and decreased activities of nonprotein thiol (NPsingle bondSH) levels, Mn-superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx) antioxidants of mitochondria. The nephroprotective efficacy of the OB leaves extract was further evident by histopathological analysis together with the PCNA-ir and Bcl2. The upshot of the present study revealed that the OB possessed significant antioxidant and nephroprotective activity and had a preventive effect on the biochemical alterations and histological changes in TAC-treated mice.

Abbreviations

ABC
Avidin-Biotin- Peroxidase
ANOVA
analysis of variance
BUN
blood urea nitrogen
DNPH
dinitrophenylhydrazine
DPPH
2,2-Diphenyl-1-picrylhydrazyl
EOBPV
Egyptian Organization for Biological Products and Vaccines
GPx
glutathione peroxidase
GSH
glutathione
H&E
hematoxylin and eosin
H2O2
hydrogenperoxide
IAEC
Institutional Animals Ethics Committee
IC
inhibitory concentration
Ip
intraperitoneal
mLPO
mitochondrial lipid peroxidation
Mn-SOD
Mn-superoxide dismutase
NP-SH
nonprotein thiol
OB
Ocimum basilicum
OPA
orthophosphoric acid
PC
protein carbonyl
PCNA-ir
proliferating cell nuclear antigen immunoreactivity
ROS
reactive oxygen species
TAC
tacroliums

Keywords

Tacrolimus
Nephrotoxicity
PCNA
Bcl-2
Ocimum basilicum

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