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Ivermectin was recommended in high doses for treatment of SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 and as a part of feed in fish farms that exposed the treated animal or human for risk of its toxicity. It can cause hepatotoxicity, renal toxicity and other side effects, which may require prompt intervention for removal. Therefore the current study aimed to investigate the potential protective effects of folic acid (FA) and vitamin B12 (Vit.B12) against IVM-induced hepatotoxicity and renal toxicity in rats after prolonged high-dose exposure. 28 male Albino rats were divided into four groups of seven rats for each group. The first group is the control group (Ctrl group) received distilled water, the second group was subcutaneously injected with IVM (IVM group), the third group was subcutaneously injected with IVM and orally administered FA (IVM\u2009+\u2009FA group), and the fourth group was subcutaneously injected with IVM and intramuscular injection of Vit.B12 (IVM\u2009+\u2009Vit.B12 group). After 30 days of the experiment, blood samples were collected for biochemical analysis while liver and kidney tissue specimens were collected for oxidative analysis and histological investigation. In addition, immunohistochemistry assays of caspase3, BAX protein, Bcl2 protein and PCNA were checked. Results revealed that IVM group displayed significant increase in the liver enzymes (AST and ALT) associated with decreased albumin, total protein and alkaline phosphatase in the serum. All kidney parameters were found significantly increased. In addition, significant increase was observed in malondialdehyde combined with significant decrease of catalase, total antioxidant capacity and superoxide dismutase in the IVM group. IVM group showed histological and immunohistochemical changes in the liver and the kidney compared to the control group. Immunoexpression of caspase3 and BAX were enhanced after administration of IVM while Bcl2 protein and PCNA were negatively expressed. All of these above mentioned parameters were almost returned to normal levels after administration of FA and Vit.B12 associated with improvement in liver and kidney function. These findings highlight the ameliorative effects of FA and Vit.B12, emphasizing the necessity of their co-administration with IVM to maximize its therapeutic benefits-including promoting food security-while minimizing its harmful effects on the liver and kidneys during treatment protocols.<\/jats:p>","DOI":"10.1038\/s41598-025-23047-2","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T11:21:54Z","timestamp":1761909714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ameliorative effect of folic acid and vitamin B12 against Ivermectin-induced hepatotoxicity, renal toxicity, oxidative stress and immunohistochemical changes in male albino rats"],"prefix":"10.1038","volume":"15","author":[{"given":"Rana A.","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahia A.","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeinab A.","family":"Mar\u2019ie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa M.","family":"Mosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seham A.","family":"Mobarak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"23047_CR1","doi-asserted-by":"publisher","first-page":"e14122","DOI":"10.15252\/emmm.202114122","volume":"13","author":"GD De Melo","year":"2021","unstructured":"De Melo, G. 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