Protective role of chrysin in sodium valproate-induced kidney injury: modulation of stress response pathways, toxicity pathways and inflammation

Sodium valproate (SVP) is a broad-spectrum antiepileptic commonly used in the treatment of numerous psychiatric disorders, notably epilepsy. Despite its therapeutic benefits, SVP has been known to cause undesirable side effects in multiple organs, particularly the kidneys. Chrysin (CHR), a natural flavonoid, is notable for its flavonoid properties which include phytotherapeutic, pharmacological, biological and aromatic characteristics; it possesses a protective capacity against organ damage due to its antioxidant, anti-inflammatory and antiapoptotic actions. The study examined the potential protective effects of CHR against SVP-induced renal damage and sought to elucidate the molecular mechanisms underlying these effects. In the study, 35 Wistar-Albino rats were used and the animals were randomly divided into five groups: Control, CHR (50 mg/kg), SVP (500 mg/kg), SVP + CHR25 (SVP + 25 mg/kg CHR) and SVP + CHR50 (SVP + 50 mg/kg CHR). All treatments were administered orally for 14 days. Blood and kidney tissue samples obtained at the end of the experiment were evaluated for biochemical, molecular, histological and immunohistochemical parameters related to oxidative stress, inflammation, apoptosis and autophagy. The findings revealed that SVP administration triggered oxidative stress (increase in MDA level) and inflammation (NF-κB, TNF-α, IL-1β expression) processes and negatively affected apoptosis-related protein levels (Caspase-3, Bax increase and Bcl-2 decrease). CHR treatment significantly improved these parameters. In addition, CHR suppressed oxidative stress by increasing the mRNA expression of NRF-2, HO-1 and NQO1 genes that regulate antioxidant defense and showed regulatory effects on the JAK2/STAT3, Wnt3/DVL-2/Cyclin D1 and Notch1/HES1 signaling pathways. Histologically, H&E staining showed that CHR administration preserved the architecture of the kidney tissue. In conclusion, the findings suggest that CHR significantly attenuates SVP-induced renal injury by reducing oxidative stress, inflammation, apoptosis and cellular degeneration. In accordance with these data, CHR may be considered as a potential protective agent against SVP-induced nephrotoxicity.