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<p>Cyclophosphamide (CP) is a chemotherapeutic and immunosuppressive agent whose clinical use is limited by hepatotoxicity and nephrotoxicity, largely mediated through oxidative stress, inflammation, and apoptosis induced by its toxic metabolites. Sitagliptin, a dipeptidyl peptidase-4 inhibitor with known antidiabetic effects, also exhibits antioxidant and anti-inflammatory properties that may confer organ protection. The present study investigated the protective effects of two different sitagliptin doses (60 and 120&#xa0;mg/kg) against chronic CP-induced hepatic and renal injury in rats and evaluated potential dose-related differences in efficacy. Chronic hepatorenal injury was induced by CP administration (5&#xa0;mg/kg/day for 50&#xa0;days). Sitagliptin was co-administered at 60 or 120&#xa0;mg/kg. Biochemical analyses included serum liver function markers (ALT, AST, ALP, total protein, albumin) and kidney function markers (urea, creatinine), along with oxidative stress parameters [malondialdehyde (MDA) and total antioxidant capacity (TAC)]. Histomorphometric assessments and immunohistochemical detection of p53 and Bcl-2 were also performed. CP administration significantly increased serum ALT, AST, ALP, urea, and tissue MDA levels while reducing total protein levels (<i>P</i> &lt; 0.05). Histopathological examination demonstrated hepatocellular degeneration, inflammatory infiltration, and renal tubular injury, accompanied by increased p53 and decreased Bcl-2 expression. Sitagliptin co-treatment attenuated several of these alterations, particularly at 60&#xa0;mg/kg, which demonstrated greater protective efficacy than the 120&#xa0;mg/kg dose across multiple biochemical, histological, and apoptosis-related parameters. In addition, sitagliptin significantly reduced renal lipid peroxidation, whereas hepatic MDA levels were not significantly improved. The superior efficacy observed with the lower dose may reflect a non-linear dose–response relationship. Conclusions: Sitagliptin exerted protective effects against chronic CP-induced hepatorenal injury, potentially through modulation of oxidative stress-related and apoptosis-associated alterations. The 60&#xa0;mg/kg dose demonstrated greater efficacy than the higher dose, highlighting the importance of dose optimization in sitagliptin-mediated tissue protection.</p>

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Protective effects of sitagliptin against cyclophosphamide-induced hepatorenal toxicity in rats: biochemical, histological, and immunohistochemical evaluation

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Fateme Esmaeili,
  • Hamid Reza Moradi,
  • Nasrin Kazemipour,
  • Mohammad Hossain Abdinasab,
  • Milad Faraji,
  • Saeed Nazifi

摘要

Cyclophosphamide (CP) is a chemotherapeutic and immunosuppressive agent whose clinical use is limited by hepatotoxicity and nephrotoxicity, largely mediated through oxidative stress, inflammation, and apoptosis induced by its toxic metabolites. Sitagliptin, a dipeptidyl peptidase-4 inhibitor with known antidiabetic effects, also exhibits antioxidant and anti-inflammatory properties that may confer organ protection. The present study investigated the protective effects of two different sitagliptin doses (60 and 120 mg/kg) against chronic CP-induced hepatic and renal injury in rats and evaluated potential dose-related differences in efficacy. Chronic hepatorenal injury was induced by CP administration (5 mg/kg/day for 50 days). Sitagliptin was co-administered at 60 or 120 mg/kg. Biochemical analyses included serum liver function markers (ALT, AST, ALP, total protein, albumin) and kidney function markers (urea, creatinine), along with oxidative stress parameters [malondialdehyde (MDA) and total antioxidant capacity (TAC)]. Histomorphometric assessments and immunohistochemical detection of p53 and Bcl-2 were also performed. CP administration significantly increased serum ALT, AST, ALP, urea, and tissue MDA levels while reducing total protein levels (P < 0.05). Histopathological examination demonstrated hepatocellular degeneration, inflammatory infiltration, and renal tubular injury, accompanied by increased p53 and decreased Bcl-2 expression. Sitagliptin co-treatment attenuated several of these alterations, particularly at 60 mg/kg, which demonstrated greater protective efficacy than the 120 mg/kg dose across multiple biochemical, histological, and apoptosis-related parameters. In addition, sitagliptin significantly reduced renal lipid peroxidation, whereas hepatic MDA levels were not significantly improved. The superior efficacy observed with the lower dose may reflect a non-linear dose–response relationship. Conclusions: Sitagliptin exerted protective effects against chronic CP-induced hepatorenal injury, potentially through modulation of oxidative stress-related and apoptosis-associated alterations. The 60 mg/kg dose demonstrated greater efficacy than the higher dose, highlighting the importance of dose optimization in sitagliptin-mediated tissue protection.