Harmine mitigates cisplatin-induced renal injury in male mice through antioxidant, anti-inflammatory, and anti-apoptosis effects

Abstract

Background and purpose: Cisplatin is a chemotherapeutic drug used to treat cancer, however, causes kidney toxicity. Harmine is a plant-derived alkaloid with a wide range of therapeutic applications. The effects of harmine on the renal side effects of cisplatin in mice were studied in this study.

Experimental approach: Forty-eight male BALB/c mice were randomly divided into eight groups (n = 6). They were treated with saline, cisplatin (5.5 mg/kg), harmine (5, 10, and 15 mg/kg/day), cisplatin + harmine (5, 10, and 15 mg/kg/day), respectively. All administrations were done daily and intraperitoneally for 4 days. The criteria related to histology, oxidation, anti-oxidation, inflammation, and apoptosis of renal tissue were evaluated.

Findings / results: There was a significant decrease in total antioxidant capacity of renal tissue, renal corpuscles diameter, and IL-10 expression level in the cisplatin group than in the control group, while the values of these parameters were significantly similar to the control group in the moderate or high doses of harmine + cisplatin groups. There were significant increases in serum urea and creatinine levels, bowman space, the amounts of malondialdehyde, apoptosis rate, and TNF-α, NF-κB, IL-1β, and caspase-3 gene expressions in kidney tissue of the cisplatin group compared to the control group, while these criteria did not differ in the moderate or high doses of harmine + cisplatin groups.

Conclusion and implications: Harmine protected the kidneys against cisplatin-induced damage. Antioxidant, anti-inflammatory, and anti-apoptotic harmine properties were involved in this healing effect.

Keywords: Antioxidants; Harmine; Oxidative stress; Toxicity.

Fig. 1

Effects of harmine (5, 10, and 15 mg/kg) and cisplatin (5.5 mg/kg) treatments on the serum creatinine and BUN levels of kidney in BALB/c mice. Values are presented as mean ± SEM; n = 6. Group 1 (control) received normal saline in a dose of 0.09%; groups 2-4 received harmine at 5, 10, 15 mg/kg, respectively; group 5 treated with cisplatin at 5.5 mg/kg; groups 6-8 received cisplatin at 5.5 mg/kg and harmine at 5, 10, and 15 mg/kg, respectively.*P < 0.05 and **P < 0.01 indicate significant differences compared to the control group; ^##P < 0.01 versus cisplatin group; ^aP < 0.05 and ^aaP< 0.01 in comparison with cisplatin + harmine (5 mg/kg) group. BUN, Blood urea nitrogen.

Fig. 2

(A) Histopathological evaluation of kidney tissue in studied groups stained by hematoxylin and eosin (× 400); yellow, blue, and white arrows are showing proteinous cast, intra-cellular vacuolization, and tubular cell detachments, respectively; yellow star is demonstrating vascular congestion; the green triangle is showing intra-tubular dilation of renal tubules. (B and C) Outcomes of harmine and cisplatin treatments on the histological characters in BALB/c mice. Group 1 (control) received normal saline in a dose of 0.09%; groups 2-4 received harmine at 5, 10, 15 mg/kg, respectively; group 5 treated with cisplatin at 5.5 mg/kg; groups 6-8 received cisplatin at 5.5 mg/kg and harmine at 5, 10, and 15 mg/kg, respectively. Values are presented as mean ± SEM; n = 6. **P < 0.01 indicates significant differences relative to the control group; ^##P < 0.01 versus cisplatin group; ^aP < 0.05 and ^aaP< 0.01 in comparison with cisplatin + harmine (5 mg/kg) group, respectively.

Fig. 3

Outcomes of harmine and cisplatin treatments on the MDA and TAC levels in the kidney tissue and the apoptotic cells in the kidneys of treated-BALB/c mice. Group 1 (control) received normal saline in a dose of 0.09%; groups 2-4 received harmine at 5, 10, 15 mg/kg, respectively; group 5 treated with cisplatin at 5.5 mg/kg; groups 6-8 received cisplatin at 5.5 mg/kg and harmine at 5, 10, and 15 mg/kg, respectively. Values are presented as mean ± SEM; n = 6. *P < 0.05 and **P < 0.01 indicate significant differences relative to the control group; ^##P < 0.01 versus cisplatin group; ^aP < 0.05 and ^aaP< 0.01 in comparison with cisplatin + harmine (5 mg/kg) group, respectively. MDA, Malondialdehyde; TAC, total antioxidant capacity.

Fig. 4

Effects of harmine (5, 10, and 15 mg/kg) and cisplatin (5.5 mg/kg) treatments on renal levels of (A-E) TNFα, NF-κB, IL-1β, IL-10, and caspase-3 in BALB/c mice. Group 1 (control) received normal saline in a dose of 0.09%; groups 2-4 received harmine at 5, 10, 15 mg/kg, respectively; group 5 treated with cisplatin at 5.5 mg/kg; groups 6-8 received cisplatin at 5.5 mg/kg and harmine at 5, 10, and 15 mg/kg, respectively. Values are presented as mean ± SEM; n = 6. *P < 0.05 and **P < 0.01 indicate significant differences relative to the control group; ^##P < 0.01 versus cisplatin group; ^aP< 0.05 in comparison with cisplatin + harmine (5 mg/kg) group, respectively. TNFα, Tumor necrosis factor-α; NF-κB, nuclear factor kappa B; IL, interleukin.