Disruption of spermatogenesis in the liver fluke, Fasciola hepatica by two artemisinin derivatives, artemether and artesunate

Abstract

An in vivo study in the laboratory rat model has been carried out to monitor changes to the spermatogenic cells in the testis tubules of adult Fasciola hepatica following treatment with the artemisinins, artemether and artesunate. Rats infected with the triclabendazole (TCBZ)-resistant Sligo isolate were dosed orally with artemether at a concentration of 200 mg/kg and flukes recovered at 24, 48 and 72 h post treatment (pt). Rats infected with the TCBZ-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200 mg/kg and flukes recovered 24, 48, 72 and 96 h pt. The flukes were processed for histological and transmission electron microscope (TEM) examination. Changes to the spermatogenic cells were evident at 24 h pt with artemether. The spermatogonial and spermatocyte cells contained abnormal mitochondria, there were fewer spermatids and spermatozoa in the tubules than normal, and a number of cells showed signs of apoptosis. There was a further decline in cell numbers at 48 h pt and the organization of the spermatocyte and spermatid rosettes was atypical. Sperm formation had become abnormal and those spermatozoa present possessed only a single axoneme. By 72 h pt, the testis tubules were vacuolated and filled with abnormal cells and cell debris. Only spermatogonial cells could be identified and there was widespread evidence of apoptosis in the cells. Distinct cellular changes following artesunate treatment did not become apparent until 48 h pt. The changes seen were similar to those described for artemether, but were generally less severe at matching time-periods. The fine structural changes occurring in the spermatogenic cells were compared to those observed in other cell types and fluke tissues and the overall information was collated to identify the cellular targets for artemisinin action and to establish the time-line for drug action.

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

“…A double-blind field trial in the Poyang Lake region (southern China) confirmed that artemether ( 3 ) significantly reduces the frequency and intensity of S. japonicum infection and does not cause side effects [ 143 ]. Despite the proven pathogenic effects on the reproductive system of Fasciola hepatica [ 144 , 145 ], artemether ( 3 ) had practically no effect in the treatment of fascioliasis in humans [ 146 ]. Artemether activity against Leishmania major [ 133 ], and Toxoplasma gondii [ 136 , 147 ] was detected; it was shown also that artemether is effective in the treatment of experimental rheumatoid arthritis [ 148 , 149 ].…”

Evaluation of the ovicidal activity and fasciolicidal activity of the extract of ethyl acetate from Artemisia ludoviciana Nutt. spp. mexicana and of artemisinin against adult parasites of Fasciola hepatica

“…and has been useful in treating Plasmodium falciparum infections in humans (Klayman 1985 ; Keizer and Utzinger 2007 ; Ferreira et al 2011 ). Studies have been carried out with artesunate and artemether, which are semisynthetic derivatives of artemisinin, against F. hepatica , and an interruption in spermatogenesis in the adult flukes, affecting their reproductive system, was observed (O’Neill et al 2009 , 2015a , b , 2017 ). In another experiment, artemether caused extensive damage to the tegument of F. hepatica (Keiser and Morson 2008 ).…”

Recent pharmacological advances in the repurposing of artemisinin drugs

“…The combination of artesunate or artemether with triclabendazole has also demonstrated synergistic effects against Fasciola hepatica . The potential mechanisms of artemisinins in this role may be related to free radical formation, changes in mitochondria, and inhibition of Na + /K + ‐ATPase activity 52,53 …”