Betaine Mitigates Cyclophosphamide-Induced Hepatotoxicity via Antioxidant Restoration and Modulation of Wnt3A/Lrp5 Signaling Pathways in Rats

Öz

Objective: Cyclophosphamide (CP) is an effective alkylating agent used in the treatment of malignancies and autoimmune diseases. However, toxic metabolites generated during hepatic metabolism induce oxidative stress, inflammation, and apoptosis, leading to hepatotoxicity that limits its clinical use. Betaine (BTN), a natural methyl donor found in foods such as beets, spinach, and wheat, has antioxidant, anti-inflammatory, and anti-apoptotic properties. This study investigated the protective effects of BTN against CP-induced liver injury in rats. Methods: Thirty-five Wistar albino rats were randomly assigned to five groups: Control, BTN, CP, CP+BTN125, and CP+BTN250. BTN (125 or 250 mg/kg) was administered orally for seven days, while CP (200 mg/kg) was injected intraperitoneally as a single dose on day 7. Blood and liver samples were collected for biochemical, molecular, and histopathological analyses. Serum AST and ALT activities; tissue MDA, SOD, CAT, GPx, and GSH levels; gene expression by RT-PCR; and histopathological changes were evaluated. Results: CP significantly increased ALT, AST, and MDA levels while decreasing SOD, CAT, GPx, and GSH levels (p<0.05). BTN improved these parameters in a dose-dependent manner, with 250 mg/kg showing greater efficacy (p<0.05). TNF-α and NF-κB expression increased in the CP group but was significantly suppressed by BTN (p<0.05). BTN also reduced apoptosis by decreasing Bax and caspase-3 expression and increasing Bcl-2 expression (p<0.05). Moreover, Wnt3A and Lrp5 expression, reduced by CP, was significantly restored following BTN treatment (p<0.05). Histopathological examination confirmed that BTN markedly attenuated CP-induced liver damage. Conclusion: BTN exerted significant hepatoprotective effects against CP-induced liver injury through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, suggesting its potential as a supportive therapeutic strategy for reducing CP-associated hepatotoxicity

Anahtar Kelimeler

• Cyclophosphamide
• Betaine
• Apoptosis
• Inflammation
• Hepatotoxicity

Kaynakça

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