The therapeutic potential of atorvastatin in treatment of G. lamblia infected mice; in silico, parasitological, and histopathological study

Abstract

Background Giardia lamblia infection (giardiasis) remains a significant global health concern, and the emergence of drug resistance to the first-line treatment, Metronidazole (MTZ), necessitates the exploration of alternative therapeutic agents. This study investigates the potential of Atorvastatin, as a repurposed drug for giardiasis, focusing on its direct antiparasitic activity and its role in modulating the associated inflammatory pathology. Methods Molecular docking simulations were performed to assess the binding affinity of Atorvastatin and MTZ against four key enzymes in the G. lamblia mevalonate pathway, which are farnesyl transferase (ftase), isopentenyl pyrophosphate isomerase (ipp), mevalonate diphosphate decarboxylase (mvd), and mevalonate kinase (mvk). An in vivo experimental model utilized Swiss albino mice infected with G. lamblia and treated with MTZ (120 mg/kg/day for 7 days) or Atorvastatin (20 mg/kg/day and 40 mg/kg/day for 5 days) was used. Efficacy of treatments was evaluated by quantifying intestinal trophozoite counts. Furthermore, the study assessed liver function (ALT/AST), intestinal and liver histopathology, and the expression of the inflammatory markers inducible Nitric Oxide Synthase (iNOS) and interleukin 6 (IL 6) in the intestinal tissues. Results Molecular docking revealed that Atorvastatin exhibited comparable or slightly superior binding affinities to the targeted G. lamblia enzymes compared to MTZ, with the strongest interaction observed with ipp_v6th89 (−5.7 kcal/mol). In vivo , Atorvastatin demonstrated significant, dose-dependent antiparasitic activity, achieving a 41.54% reduction in trophozoite counts at 40 mg/kg, though this was lower than the 71.73% reduction achieved by MTZ. Crucially, Atorvastatin exhibited a superior anti-inflammatory effect. The higher dose of Atorvastatin suppressed iNOS expression to 5.40% of the reaction area, a nearly four-fold reduction compared to the infected untreated group (19.59%) and significantly better than the modest reduction seen with MTZ (17.49%). On the other hand, Atorvastatin (at a dose of 40 mg /kg) proved to be the most potent intervention, suppressing IL-6 expression to a low average of 6.12% in comparison to 26.7 and 17.6% reaction area for infected untreated and MTZ treated mice, respectively. Histopathological analysis confirmed that Atorvastatin treatment effectively restored intestinal architecture and mitigated liver pathology, correlating with a significant reduction in elevated serum ALT levels. Conclusion Atorvastatin possesses a dual therapeutic role against giardiasis. It acts as a moderate antiparasitic agent, likely by targeting the mevalonate pathway, and as a potent immunomodulatory agent. Its superior ability to suppress the inflammatory response and mitigate intestinal and hepatic pathology suggests that Atorvastatin is a promising candidate for an adjunct therapy to Metronidazole, particularly in cases where inflammation and chronic sequelae are major concerns.