Syringaldehyde Mitigates Cyclophosphamide-Induced Liver and Kidney Toxicity in Mice by Inhibiting Oxidative Stress, Inflammation, and Apoptosis Through Modulation of the Nrf2/HO-1/NFκB Pathway

Abstract

Cyclophosphamide (CYC) is one of the most potent antineoplastic drugs; however, hepatonephrotoxicity, observed following its use, remains one of its most severe side effects. Previous studies have reported that syringaldehyde (SYA), a flavonoid compound, exhibits anti-inflammatory and antioxidant properties. However, it is unclear whether SYA has any effects on hepatonephrotoxicity caused by the side effects of antineoplastic drugs. In the present research, we thoroughly evaluated the effects of SYA on cyclophosphamide-induced hepatonephrotoxicity in a mouse model, focusing on Nrf2/HO-1 pathway activation. In the present study, SYA (25 and 50 mg/kg, p.o.) and CYC (30 mg/kg, i.p.) were delivered to male mice for 10 days to induce hepatonephrotoxicity. SYA treatment alleviated the elevated levels of AST, ALT, BUN, and creatinine caused by CYC. It further suppressed lipid peroxidation by lowering MDA levels and enhanced antioxidant defense by elevating GSH, SOD, and CAT levels. Additionally, SYA increased the mRNA expression levels of HO-1, Nrf2, and Bcl-2, which had been reduced due to oxidative stress, inflammatory, and apoptotic pathways, while suppressing the elevated gene expression levels of NF kappa B, TNF-alpha, Bax, and Cas-3. Furthermore, SYA regulated the altered protein expression levels of Nrf2, Cas-3, Bax, and Bcl-2 induced by CYC. Microscopically, SYA also mitigated liver and kidney tissue damage caused by CYC. In conclusion, SYA significantly reduced CYC-induced hepatonephrotoxicity by inhibiting inflammation, oxidative stress, and apoptosis by employing the Nrf2/NF kappa B/HO-1 pathway. These findings indicate that SYA has the possibility as a treatment option agent in the case of prevention of liver and kidney damage.