Studies on Parasitologic and Haematologic Activities of an Enaminone Derivative of 4-Hydroxyquinolin-2(1H)-one Against Murine Schistosomiasis Mansoni

Amal M. El–Shennawy, MD; Amira H. Mohamed, MD; Mohamed Abass, MD

Disclosures
In This Article

Discussion

For schistosomiasis, vaccine is nonexistent and drugs remain the mainstay of disease control. However, the current drug repertoire is limited and/or inadequate, and the problem is being further exacerbated by the emergence of drug resistance. Because of this phenomenon, it remains an urgent necessity to find new compounds that show particularly good efficacy against schistosomiasis with minimal toxicity.

1–Butyl–3–[2E–3–(dimethylamino)prop–2–enoyl]–4–hydroxyquinoline–2(1H)–one (BDHQ) showed more potency against hatchability of B alexandrina egg masses, the infection rate, and prepatent period of the snails. In addition, this derivative revealed potential larvicidal effects (100% mortality) on both miracidia and cercariae of Schistosoma mansoni at reduced exposure time.[7]

In the present study, we tried to screen –– by electron microscopy and parasitologic study –– BDHQ for its potential activity against S mansoni in a murine model of infection, and we correlated this study with serum levels of IFN–gamma and IgE to evaluate both humoral and cellular immune responses. We compared its effect with that of PZQ, which is the agent of choice in the treatment of schistosomiasis as it is highly effective against both species of schistosome and has low toxicity.[2]

In this study, the various parasitologic criteria indicated the in vivo antischistosomal effects of 2 BDHQ dosing regimens: both doses caused significant reductions in mature and immature worm loads and tissue egg loads compared with control and in immature worms compared with the PZQ–treated group, while the group treated with a higher dose showed significant reductions in intestinal ova count compared with the PZQ–treated group.

So both mature and immature worms are targets for the action of BDHQ, in contrast to the effects of the recognized antischistosomal drug PZQ, which kills only adult schistosomes.[2]

Ultrastructural study of the worms revealed a significant destructive effect of either BDHQ or PZQ on worm tegument, whereas BDHQ only has significant destructive effects on the female and male genital systems in the form of pycnosis of germinal vesicles of the oocytes and vaculation and necrosis of spermatocyte. Jürg and colleagues[13] reported that PZQ could produce contraction and paralysis of helminths by affecting membrane permeability to calcium.

Gamma interferon is a Th1 cytokine that can activate macrophages to produce NO and other inflammatory mediators.[14] Zhang and colleagues[15] found that IFN–gamma may suppress liver fibrogenesis induced by upregulation of TGF–beta1 in mice infected by Schistosoma, so it may be effective in the treatment of hepatic fibrosis. Similarly, Henri and colleagues[16] reported that IFN–gamma is certainly the most powerful and most active antifibrogenic cytokine in the experimental schistosome egg granuloma, and they also observed that IFN levels are inversely related to infection associated with periportal fibrosis, so the high rate of infections may contribute to periportal fibrosis by downmodulating IFN–gamma.

In our study, serum levels of IFN–gamma significantly increased in BDHQ–treated groups in comparison to the control group, and no significant difference was detected between the BDHQ– and PZQ–treated groups. The rise of serum levels in the treated groups could be attributed to an overall activation of the immune system, as suggested by Lins de Morais and colleagues.[17] Ribeiro de Jesus and colleagues[18] supported the role of IFN–gamma production in the protective response in human beings by showing higher levels of this cytokine in partially or completely resistant subjects, and they also suggested that IFN–gamma in humans stimulates the production of IgG2, which may be involved in the protective immunity.

With regard to serum levels of anti–SWAP IgE, a significant increase was observed in the BDHQ–treated groups compared with the control and the PZQ–treated groups. Naus and colleagues[19] reported that IgE responses against the adult worm were associated with resistance to reinfection after chemotherapy. Previous studies of S mansoni in Senegal and Kenya[20] showed no association between specific IgE responses and pretreatment infection intensity, while in studies in Brazil and the Sudan,[21] a positive correlation was found. Capron[22] found that specific IgE, interacting with eosinophils and phagocytic cells, has been demonstrated to be effective in schistosomula destruction in vitro and may be an important immune defense mechanism in the skin, where these cell types are found at the time of cercarial penetration. Bahia–Oliveira and colleagues[23] and Demeure and colleagues[6] found that high levels of both specific IgE in sera and IFN–gamma in antigen–stimulated peripheral blood mononuclear cell cultures were associated with high resistance to reinfection.

In this study, our results of IgE and IFN–gamma in sera were confirmed by the ultrastructural study of peripheral blood, bone marrow, liver, and spleen, which imply evident features of cellular activation in treated groups compared with the infected, untreated group. Also, the increasing number of follicular dendritic cells in the BDHQ–treated spleens, in addition to promonocyte activation in the bone marrow and activated monocytes in peripheral blood, might be consequence of the significant increase of IFN–gamma secreted by activated T lymphocytes by the novel hydroxyquinoline derivative (BDHQ). These findings are supported by Sher and colleagues,[4] who reported the role of T helper 1 (Th1) in production of IFN–gamma that activate macrophages as part of a delayed type hypersensitivity reaction, the reaction was reported to provide protection against S mansoni infection in mice. On the other hand, Biggelaar and colleagues[24] studied the role of dendritic cells in chronic schistosomiasis and reported that schistosome–specific T–helper cells are present in the periphery but are functionally hyporesponsive during active infection with schistosomes and cytokine responses representing the Th1 and, more importantly, Th2 types can be restored by dendritic cells. Also, the intimate contact of dendritic cells with lymphocytes, as seen on electron microscopy, was confirmed by Colley and colleagues,[25] who reported the role of dendritic cells as critical antigen–presenting cells for the induction and control of immune responses and demonstrated that schistosomes can induce elevated percentages of PD–L2 (B7–DC), which is a regulatory ligand on subpopulations of dendritic cells and binds to the coregulatory receptor PD–1, present on some activated T lymphocytes, leading to downregulation. In addition, BDHQ–treated spleens revealed a remarkable increase of longitudinal intracellular contractile filaments in the endothelial cells lining the splenic sinus, so the interendothelial slits that are normally narrow or even closed[26] are forced apart by endothelial contraction, thereby increasing the blood flow from the filtration bed and into the vein through these slits. The increased longitudinal intracellular contractile filaments in the endothelial cells may be attributable to the increased stimulation of nitric oxide synthesis in endothelial cells by hydroxyquinoline via an impairment of iron metabolism that stimulates glutathiolation of cytoskeletal and mitochondrial proteins,[27] in addition to the role of hydroxyquinoline in Mg2+ and Zn2+ regulation that allow dynamic regulation of actin microfilament organization.[28]

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