Protective Effects of Trimetazidine Against Acetaminophen-Induced Liver Injury in Mice
Acetaminophen (APAP) overdose accounts for many cases of acute liver injury. The aim of the present study was to explore the possible hepatoprotective effect of trimetazidine, an anti-ischemic antianginal agent, against APAP-induced acute hepatotoxicity. Mice (n = 6) received trimetazidine (10 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of APAP (750 mg/kg). Mice receiving saline (n = 6) and non-treated APAP group (n = 10) served as controls. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), γ-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), total proteins and albumin were determined. Hepatic total nitrite/nitrate (NOx) and antioxidant status were assessed and histological analyses were performed. Hepatic levels of interleukin-6 (IL-6) were assayed by ELISA. The hepatic tissue expression of tumor necrosis factor-α (TNF-α) was identified immunohistochemically. Pre-treatment with trimetazidine prevented APAP-induced mortality. It also attenuated APAP-induced liver injury in mice as revealed by significantly inhibiting APAP-induced elevations in serum levels of ALT, AST, LDH, γ-GT and ALP and hepatic malondialdehyde and IL-6 contents. In addition, it significantly ameliorated APAP-induced reductions in serum levels of albumin and total proteins and hepatic levels of reduced glutathione, superoxide dismutase and NOx. Moreover, trimetazidine-treated mice showed reduced hepatic expression of TNF-α compared to APAP group. Trimetazidine effectively preserved tissue morphology as evidenced by histological evaluation. In conclusion, trimetazidine mitigated acute liver injury induced by APAP overdose in mice, a hepatoprotective effect which can be attributed to inhibition of oxidative stress and the proinflammatory cytokine TNF-α- and IL-6-dependent inflammation.
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Document Type: Research Article
Publication date: March 1, 2017
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