Abstract
Background and objective: Tyrphostin "AG1024" is an insulin growth factor-1 receptor (IGF-1R) inhibitor that displayed an effect on the viability of larval and mature schistosomes in vitro. We sought to investigate the possible in vivo role of AG1024 as a potential new anti-Schistosoma drug against immature and adult stages of Schistosoma mansoni and its effect on the degree of hepatic fibrosis and insulin pathway.
Methods: The study included a control non-infected group and 5 groups of S. manosoni-infected CD-1 albino mice (20 mice each) assigned to treatment as follows: vehicle-treated, early AG1024, 30 mu g/100 mu l DMSO, IP for 10 days started 30 days post-infection (dpi), early praziquantel (PZQ), 500 mg/kg orally for 2 days (30 dpi), late AG1024 (60 dpi), and late PZQ (60 dpi). All mice were sacrificed 12 weeks post-infection. Parasitological, chemical and histopathological parameters were studied. Immunohistochemistry of TGF-beta and GLUT4 in liver sections was done to further evaluate the effect of AG1024 on the degree of hepatic fibrosis and insulin signaling pathway, respectively.
Results: Early administration of AG1024 (30 dpi) resulted in significant reduction of hepatic and intestinal tissue egg count with a reduction of 79.99% and 89.1% respectively. Late administration of AG1024 (60 dpi) led to 77.78% reduction of intestinal eggs count; however, hepatic egg count wasn't reduced significantly. No reduction in worm burden was recorded for both administration regimens. Both regimens lead to significant decrease of both ALT and AST, mean hepatic granuloma diameter but an increase in fibrosis percentage (65.2% and 55% respectively). Both early and late treatment with AG1024 showed a significant increment of TGF-beta expression by 71.4% and 39.3%, respectively (p < 0.0001) compared to PZQ-treated and infected non-treated groups. Hepatic GLUT4 expression was significantly decreased compared to infected non-treated group (p < 0.001) and the corresponding PZQ-treated group.
Conclusion: Early AG1024 administration induced more significant results compared to early PZQ with a promising activity against egg production and subsequent reduction of tissue egg load rather than direct schistosomicidal effect; however, it induced granuloma fibrosis, TGF-beta expression, and disrupted the insulin signaling pathway.