Dose-response relationship in Schistosoma mansoni juvenile and adult stages following limonin treatment in experimentally infected mice

Abstract

Preventive chemotherapy with praziquantel is the mainstay of schistosomiasis control. However, drug resistance is an imminent threat, particularly with large-scale administration of praziquantel, in addition to much less efficacy against young schistosomes. Several biological activities of limonin have been explored such as insecticidal, insect antifeedant, and growth-regulating activity on insects as well as antimalarial, antiviral, anticancer, cholesterol-lowering, and antioxidant activities. This study investigates limonin as an alternative antischistosomal compound using two novel, single, oral dose regimens. In the current work, the therapeutic efficacy of different limonin dosing protocols was evaluated in experimentally infected mice harboring Schistosoma mansoni (Egyptian strain) juvenile or adult stages. Oral administration of limonin in a single dose of 50 or 100 mg/kg on day 21 post-infection (p.i.) resulted in a significant worm burden reduction of 70.0 and 83.33 %, respectively. The same dose given on day 56 p.i. reduced total worm burdens by 41.09 and 60.27 %, respectively. In addition, significant reductions of 34.90 and 47.16 % in the hepatic and 46.67 and 56.1 % in the intestinal tissue egg loads, respectively, associated with significant alterations in the oogram pattern with elevated dead egg levels. Limonin produced ameliorations of hepatic pathology with reduction in dimensions and number of granulomas. Limonin also produced a variety of tegumental alterations in treated worms including tubercular disruption, edema, blebbing, and ulcerations. Results obtained by this work elucidated promising limonin bioactivity against S. mansoni juvenile and adult stages and provided a basis for subsequent experimental and clinical trials.

Tegumental changes induced in adult S. mansoni by limonin: animal experimental and electron microscopic studies

“…Oral administration of limonin to S. mansoni experimentally infected mice resulted in worm burden reduction and significant reductions in both hepatic and intestinal tissue egg loads with elevated dead egg levels. Limonin also produced reduction in dimensions and number of hepatic granulomas [39] . In the present study, we investigated the in vitro schistosomicidal activity of pure limonin compound against adult S. mansoni worms.…”

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs

“…Besides the antischistosomal activity, it has been demonstrated that antioxidants are capable of restoring the activity of antioxidant liver enzymes near to the levels detected on controls [107,109,117,119,126,[129][130][131]. The increase of antioxidant enzymes activity is usually accompanied by reduction on granuloma size and number, resulting in improvement of the liver architecture and functions [108,125,128,129,132,133].…”

“…In addition, they support internal organs including the reproductive, excretory and digestive tracts, and maintenance of the female within the gynecophoral canal of the male [121,122]. It was also observed that antioxidants are capable of inducing severe tegumental alterations [108,111,117,120], which is a crucial organ for protection against host responses, nutrient uptake for parasite development and growth, and plays an important role in host-parasite interaction [123]. Moreover, antioxidants impaired worm coupling [113,114,116,124], a process fundamental to oviposition [107,120,[125][126][127][128].…”

“…Most of the antioxidants assessed have shown potential antischistosomal activity either in vitro and in vivo, not only against mature [107][108][109][110][111][112][113][114][115][116] as well as in immature forms of S. mansoni and S. japonicum [113,[117][118][119]. These studies have demonstrated that some antioxidants affect the motor activity of the worm in vitro, revealing a possible perturbation/dysfunction of elements of the neuromuscular system [120].…”

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules

“…In recent times, studies evaluating efficacy of antioxidants, alone or concurrently with antischistosomal drugs targeting not only parasite but also pathologies associated to infection have been reported [ 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ] ( Table 1 and Figure 5 ).…”