Five-day administration of ivermectin is effective in attenuating valproic acid-induced liver toxicity in rats
DOI:
https://doi.org/10.1590/Keywords:
Ivermectin, Valproic acid, Weight gain, Fatty liverAbstract
Valproic acid (VPA) is an effective and inexpensive anticonvulsant commonly prescribed as an antiepileptic. However, there is a percentage of susceptible patients who experience unwanted effects, such as weight gain and fatty liver. Ivermectin (IVM), a versatile antiparasitic, has shown potential in the treatment of non-alcoholic fatty liver disease. In this study, the potential hepatoprotective effect of ivermectin on valproic acid-induced hepatotoxicity was investigated in rats. VPA (250 mg/kg/day) was orally administered for 14 consecutive days to induce hepatocellular damage in adult Wistar rats, after which the animals were treated with a subcutaneous injection of IVM (0.4 and 1.3 mg/kg/day) for another five days. Animals receiving VPA developed obesity and microvesicular and macrovesicular steatosis. They also had increased levels of plasma triglycerides and aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase enzymes. IVM treatment significantly decreased serum triglyceride and cholesterol levels and attenuated valproic acid-induced hepatic lipid accumulation in rats. These results were confirmed by histopathological examination.
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Abdelkader NF, Elyamany M, Gad AM, Assaf N, Fawzy HM, Elesawy WH. Ellagic acid attenuates liver toxicity induced by valproic acid in rats. J Pharmacol Sci. 2020; 143: 23-29.
Arise RO, Malomo SO. Effects of ivermectin and albendazole on some liver and kidney function indices in rats. Afr J Biochem Res. 2009; 3(5): 190-197.
Chang R, Chou M, Hung L, Wang M, Hsu M, Chiu C. Study of valproic acid-enhanced hepatocyte steatosis. BioMed Res Int. 2016; 9576503.
Culling CFA. Hand Book of Histopathological Techniques, 2nd edition, Butterworth, London; 1965.
Dong Z, Xing S, Zhang J, Zhou X. 14-Day Repeated intraperitoneal toxicity test of ivermectin microemulsion injection in wistar rats. Front Vet Sci. 2020; 7: 598313.
Frankel. Gradwohl’s Clinical laboratory methods and diagnostic, 7ª Ed vol 1, - Ed. Frankel, Reitman y Sonnenwirth; 1970.
Guo HL, Jing X, Sun JY, Hu YH, Xu ZJ, Ni MM, et al. Valproic acid and the Liver injury in patients with epilepsy: An Update. Curr Pharm Des. 2019; 25(3): 343-351.
Haschek WM, Rousseaux CG. Fundamentals of Toxicologic Pathology. 2nd ed. San Diego, CA: Academic Press; 2010.
Jin L, Feng X, Rong H, Zhifu P Yuka I, Qui L, et al. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun. 2013; 4: 1937.
Jin L, Wang R, Zhu Y, Zheng W, Han Y, Guo F, et al. Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease. Sci Rep. 2015; 5: 17288.
Laing R, Gillan V, Devaney E. Ivermectin – Old Drug, new tricks? Trends in Parasitology. 2017; 33(6): 463-472.
Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009; 47(2): 101-11.
Melotti A, Mas C, Kuciak M, Lorente-Trigos A, Borges I, Ruiz I et al. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med. 2014; 6(10): 1263-1278.
Maneenin C, Lapyuneyong N, Tongpan S, Yannasithinon S, Burawat J, Maneenin N, et al. The Alterations of Microvasculature, Tyrosine Phosphorylation, and Lipid Peroxidation in Kidney of Rats Treated with Valproic Acid. Int J Morphol. 2019; 37(1): 65-70.
Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem. 2013; 46(15): 1323-1338.
Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord. 2022; 22(1): 63.
Qi W, Clark JM, Suvorov A, Park Y. Ivermectin decreases triglyceride accumulation by inhibiting differentiation of 3T3-L1 preadipocytes. Food Chem Toxicol. 2019; 131: 110576.
Tolou-Ghamari Z, Palizban AA. Review of sodium valproate clinical and biochemical properties. Zahedan J Res Med Sci. 2015; 17(8): e2207.
Trinder PA. Simple turbidimetric method for the determination of serum cholesterol. Ann Clin Biochem. 1969; 6: 165-166.
Yang JS, Qi W, Farias-Pereira R, Choi S, Clark JM, Kim D, et al. Permethrin and ivermectin modulate lipid metabolism in steatosis-induced HepG2 hepatocyte. Food Chem Toxicol. 2019; 125: 595-604.
Zhu MM, Li HL, Shi LH, Chen XP, Luo J, Zhang ZL. The pharmacogenomics of valproic acid. J Hum Genet. 2017; 62: 1009-1014.
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