The metalloprotease inhibitor 1,10-phenanthroline affects Schistosoma mansoni motor activity, egg laying and viability

Abstract

The Zn²⁺-chelating metalloprotease inhibitor 1,10-phenanthroline (phenanthroline, 5–150 μM) elicited dose-dependent contraction of the longitudinal and circular (transverse) musculature of adult male schistosomes. At the same concentrations, phenanthroline did not cause contraction of dispersed individual muscle fibres. The phenanthroline-induced contractions were reduced by the inclusion of 100 or 300 μM Zn²⁺ in the extracellular medium. Phenanthroline (0·5–150 μM) also inhibited the egg production of adult worm pairs in vitro, with a 98% reduction at 50 μM. When worm pairs were exposed to phenanthroline, the males detached from the dish and released the females, resulting in unpaired worms. At the higher concentrations (50 and 150 μM), the worms were killed in vitro. Worm burdens were reduced by over 50% in infected mice injected with phenanthroline (20 mg/kg/day for 4 days), but twice the dose resulted in only a 25% reduction. Phenanthroline injections also induced an hepatic shift and an unpairing of adult worms in infected mice, and the female worms appeared degenerate and lacked gut pigmentation. Mice fed a diet containing 0·3% phenanthroline received significant protection from infection when challenged with schistosome cercaria, where phenanthroline-fed mice had 94% fewer adult worms than control mice. The broad range of phenanthroline effects on schistosomes suggests broad and important functions for metalloproteases in these worms.