Investigation of the therapeutic effect of Hypericum perforatum (st. john's wort) on cisplatin-induced nephrotoxicity in mice by molecular and pathological methods

Cisplatin (CP) is the first of the platinum-group drugs frequently preferred in cancer treatment, but its nephrotoxic side effects are the main factor limiting its clinical use. This study aimed to investigate the therapeutic efficacy of Hypericum perforatum (HP) on cisplatin-induced nephrotoxicity through apoptosis and antioxidant parameters and histopathological findings. In the study, 42 male Swiss mice, 8-10 weeks old, were randomly assigned to 6 groups: 6 mice each in groups 1, 2, and 3, and 8 mice each in the other experimental groups. Group 1: Control; Group 2 (vehicle control): 5% DMSO solvent administered intraperitoneally (po) for 10 days; Group 3 (HP control): 400 mg/kg HP administered po for 10 days; Group 4 (SP): 10 mg/kg SP administered intraperitoneally (i.p.) as a single dose on day 6; Group 5 (prophylaxis): 400 mg/kg HP for 10 days, po. + 10 mg/kg SP as a single dose ip on day 6; Group 6 (treatment): 10 mg/kg SP as a single dose ip on day 6, + 400 mg/kg HP as a single dose ip on day 6, were administered via po gavage from day 6 until day 10. Following blood collection on day 11, all animals were euthanized and necropsied. Right kidneys were placed in 10% formalin for histopathological examination, and left kidneys were stored in liquid nitrogen tanks at -80°C for molecular examination. Caspase-3 levels were assessed to determine the effectiveness of apoptosis, and expression levels of the Nrf2/HO-1 pathway were assessed by RT-PCR to determine the effectiveness of oxidative stress. MDA levels and total antioxidant capacity (TAC) were measured by ELISA as markers of lipid peroxidation in kidney tissue. In the SP group, serum BUN and creatinine levels increased significantly (p<0.05), while TAC levels decreased significantly, while despite an increase in MDA levels, no statistically significant difference was observed. HP administration combined with SP resulted in a significant decrease in serum BUN and creatinine levels (p<0.05), which was more pronounced in the prophylaxis group. HP administration increased TAC levels in the cisplatin groups (p<0.05), while no significant change in MDA levels was observed. PCR measurements revealed a decrease in caspase-3 gene expression in the prophylaxis and treatment groups compared to the SP group, but there was no statistically significant difference. Nrf2 expression increased in the SP and treatment groups, while it decreased significantly in the prophylaxis group. A significant increase in HO-1 expression was detected in the SP group. This expression decreased with HP administration, and the decrease in the prophylaxis group was significant (p<0.05). Histopathological examination revealed the highest incidence of necrosis and vacuolization in the tubular epithelium, and hyaline casts in the tubular lumen, in the SP group. Significant improvements were observed in the prophylaxis group. Based on the biochemical, molecular, and histopathological findings obtained in the study, it was concluded that Hypericum perforatum may have a renoprotective potential against cisplatin-induced nephrotoxicity by regulating oxidative stress by inducing antioxidant genes and enzymes, and that prophylactic administration is particularly beneficial.