RESUMEN
In contrast to young rats, adult rats given i.p. Plasmodium berghei Anka (PbA) control the parasitaemia and repair their anaemia. Here, we investigated whether IgE and CD23/NO immune pathway could be implicated in this age-related resistance of adult rats to PbA. Eight-week-old rats displayed significantly higher levels of plasma total IgE (p=0.01) and soluble CD23 (p=0.003) during the peak of parasitaemia, compared to 4-week-old rats. IgE Fc-binding antibody or aminoguanidine administration to parasitized 8-week-old rats slightly delayed blood parasite clearance or exacerbated anaemia. These data suggest that IgE and CD23/NO could play an important role in the resistance of adult rats experiencing PbA primary intraerythrocytic development.
Asunto(s)
Envejecimiento/inmunología , Inmunoglobulina E/sangre , Malaria/inmunología , Óxido Nítrico/metabolismo , Parasitemia/inmunología , Plasmodium berghei/patogenicidad , Receptores de IgE/sangre , Animales , Eritrocitos/parasitología , Femenino , Malaria/parasitología , Parasitemia/parasitología , Ratas , Ratas Endogámicas Lew , Organismos Libres de Patógenos EspecíficosRESUMEN
An original series of 4-substituted pyrrolo[1,2-a]quinoxaline derivatives, new structural analogues of Galipea species quinoline alkaloids, was synthesized from various substituted 2-nitroanilines via multistep heterocyclizations and tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Structure-activity relationships enlighten the importance of the 4-substituted alkenyl side chain on the pyrrolo[1,2-a]quinoxaline moiety to modulate the antileishmanial activity.
Asunto(s)
Antiprotozoarios , Leishmania/efectos de los fármacos , Quinoxalinas , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Cristalografía por Rayos X , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Leucocitos Mononucleares/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinoxalinas/síntesis química , Quinoxalinas/química , Quinoxalinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In Plasmodium falciparum-infected cells or in P. berghei infected mice, increase of reduced glutathione (GSH) levels confers resistance to chloroquine (CQ). GSH is synthesized within the cells through a complex biochemical pathway composed of several well known enzymes, in which glucose-6-phosphate dehydrogenase (G6PD) plays an important role. The physiological hormone dehydroepiandrosterone sulfate (DHEAS) is a potent inhibitor of G6PD activity, and G6PD deficiency is known to exert antimalaria protection. This study aimed to investigate the ability of DHEAS to enhance the antimalarial activity of CQ, via an inhibition of G6PD activity and GSH synthesis. Two P. berghei CQ resistant strains (CQR6 and CQR30) were selected in vivo from the sensitive strain NK65. Drug effects were checked both by monitoring the evolution of parasitaemia and by the survival of infected mice. In addition, intra-parasite levels of GSH and G6PD activity were measured before and after the treatment. Results demonstrate that acquisition of CQ resistance in P. berghei is associated with a significant increase in parasite G6PD activity and GSH level. Combination of CQ with DHEAS or buthionin sulfoximin (BSO, a specific inhibitor of GSH synthesis) significantly increased sensitivity of resistant parasites to CQ and increased the survival period of the infected mice. This reduction of parasitaemia and improvement of the survival of infected mice were associated with intra-parasite depletion of GSH and inhibition of G6PD activity due to DHEAS action. This experimental study suggests that DHEAS could be used to potentiate antimalarial action of CQ, particularly on CQ resistant strains.