Achillea millefolium ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation in rats

Abstract

Background/aim: Doxorubicin (Dox) is a potent anticancer medication. However, due to nephrotoxicity, its clinical application is restricted. Achillea millefolium (AM) is a plant used in traditional medicine to treat several conditions, including kidney disorders. The aim of this work was to investigate the preventative properties of AM extract (AME) and their mechanisms against nephrotoxicity caused by Dox in rats.

Materials and methods: The rats were assigned randomly to six groups, including a control group, Dox group (5 mg/kg/week via i.p. for 4 weeks), two groups receiving AME (100 or 200 mg/kg, orally for 28 days), and the last two groups receiving Dox + AME (100 or 200 mg/kg, orally for 4 weeks). After the treatment period concluded, samples of blood and renal tissue were collected for analysis. Serum creatinine, urea, and uric acid levels were used to determine nephrotoxicity biochemically. In renal tissue samples, superoxide dismutase (SOD), catalase, glutathione (GSH), glutathione peroxidase (GPx), total antioxidant capacity (TAC), nitric oxide (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and nuclear factor kappa B (NF-κB) were measured. Histopathological analysis of the kidneys was also performed.

Results: Dox caused a considerable increase in kidney function parameters and the occurrence of histological changes, which were significantly reversed by AME treatment. Mechanistically, Dox caused renal oxidative stress by raising malondialdehyde and NOx levels while lowering SOD, GSH, GPx, and TAC. It also caused inflammation via the stimulation of proinflammatory cytokines in renal tissues. Conversely, the treatment of AME mitigated Dox-evoked abnormalities in the above-mentioned tests.

Conclusion: AME could protect against nephrotoxicity caused by Dox by reducing oxidative stress, stimulating antioxidant mechanisms, and suppressing proinflammatory cytokines, suggesting that AME may be useful as an adjuvant therapy for Dox-induced nephrotoxicity.

Keywords: Achillea millefolium; doxorubicin; inflammation; nephrotoxicity; oxidative stress.

Figure 1

Effects of AME on (A) serum uric acid, (B) creatinine, and (C) serum urea in rats treated with Dox. Results are shown as the mean ± SE (n = 8). ^***p < 0.001 vs. control group; ^###p < 0.001 vs. Dox group. [Dox, doxorubicin; AME100, Achillea millefolium extract 100 mg/kg; AME200, Achillea millefolium extract 200 mg/kg].

Figure 2

Histopathological evaluation, hematoxylin and eosin staining, A: control group, B: Dox group, C: AME100 group, D: AME200 group, E: Dox + AME100 group, F: Dox + AME100 group, scale bar: 20 μm, black arrows: glomerular degeneration and necrosis, blue arrows: proximal tubule cell degeneration necrosis, proximal tubule epithelial cells edema.

Figure 3

AME ameliorates Dox-induced kidney injury via inhibition of oxidative stress in rats through (A) SOD, (B) renal lipid peroxidase activity as MDA, and (C) catalase activity. Results are shown as the mean ± SE (n = 8). ^***p <0.001 vs. control group; ^##p < 0.01 vs. Dox group; ^###p < 0.001 vs. Dox group. [SOD, superoxide dismutase; MDA, malondialdehyde].

Figure 4

AME attenuated GSH, GPx, and TAC in rats treated with Dox, also AM treatment prevented NOx production during Dox-induced kidney injury in rat. Results are shown as the mean ± SE (n = 8). ^***p < 0.001 vs. control group; ^##p < 0.01 vs. Dox group; ^###p < 0.001 vs. Dox group. [GSH, glutathione; GPx, glutathione peroxidase; TAC, total antioxidant capacity; NOx, nitric oxide].

Figure 5

AME ameliorates inflammation in Dox-induced nephrotoxicity by inhibition of inflammatory markers; TNF-α, IL-1β, and NF-κB. Results are shown as the mean ± SE (n = 8). ^***p < 0.001 vs. control group; ^###p < 0.001 vs. Dox group. [TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1β; NF-κB, nuclear factor kappa B].