RESUMO
Data recently reported by our group indicate that stimulation with a pool of immunogens capable of eliciting type 2 immune responses can restore the cognitive and behavioral dysfunctions recorded after a single episode of non-severe rodent malaria caused by Plasmodium berghei ANKA. Here we explored the hypothesis that isolated immunization with one of the type 2 immune response-inducing immunogens, the human diphtheria-tetanus (dT) vaccine, may revert damages associated with malaria. To investigate this possibility, we studied the dynamics of cognitive deficits and anxiety-like phenotype following non-severe experimental malaria and evaluated the effects of immunization with both dT and of a pool of type 2 immune stimuli in reversing these impairments. Locomotor activity and long-term memory deficits were assessed through the open field test (OFT) and novel object recognition task (NORT), while the anxiety-like phenotype was assessed by OFT and light/dark task (LDT). Our results indicate that poor performance in cognitive-behavioral tests can be detected as early as the 12th day after the end of antimalarial treatment with chloroquine and may persist for up to 155 days post infection. The single immunization strategy with the human dT vaccine showed promise in reversal of long-term memory deficits in NORT, and anxiety-like behavior in OFT and LDT.
Assuntos
Transtornos Cognitivos , Disfunção Cognitiva , Humanos , Imunomodulação , Vacina contra Difteria e Tétano , Imunidade , CogniçãoRESUMO
C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) develop neurological symptoms and die 6--7-day post-inoculation in the absence of high parasitemia. The effects of chronic intake of a high-fat diet on this process are largely unknown. In this study, we assessed the effect of a high-fat diet on the host-parasite response to malarial infection. Mice were fed ad libitum with either standard or a high-fat diet for 8 weeks and afterwards were infected with PbA. PbA-infected mice feeding a standard diet presented blood parasitemia, hepatic and cerebral histopathological alterations, and hepatic injury with increased hemozoin deposition in the liver. By contrast, these changes were not observed in the malaria high-fat diet group. In addition, mice fed a high-fat diet did not develop the expected neurological symptoms of cerebral malaria and were resistant to death. Taken together, our results indicate that chronic ingestion of high-fat diet prevents the development of experimental malaria induced by PbA injection, suggesting a relationship between a high-fat diet and malaria, which is an interesting subject for further study in humans.
Assuntos
Dieta Hiperlipídica , Malária/prevenção & controle , Plasmodium berghei/fisiologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Hemeproteínas/metabolismo , Fígado/metabolismo , Fígado/patologia , Malária/parasitologia , Malária/patologia , Camundongos Endogâmicos C57BL , Parasitemia/parasitologia , Parasitemia/prevenção & controle , Plasmodium berghei/crescimento & desenvolvimentoRESUMO
A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP)-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3) inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.
Assuntos
Animais , Camundongos , Ratos , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Parasitemia/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Modelos Animais de Doenças , Citometria de Fluxo , Proteínas de Fluorescência Verde , Técnicas In Vitro , Malária/parasitologia , Parasitemia/parasitologiaRESUMO
Infection of mice with Plasmodium berghei NK65 represents a well-recognized malaria model in which infection is accompanied by an intense hepatic inflammatory response. Enzyme-inducible nitric oxide synthase is an important regulator of inflammation and leukocyte recruitment in microvessels, but these functions have yet to be evaluated in experimental malaria. In this study, we assessed the involvement of inducible nitric oxide synthase in inflammatory responses to murine experimental malaria induced by P. berghei NK65. We observed that wild type (WT) and nitric oxide synthase (iNOS)-deficient mice (iNOS(-/-)) mice showed similar levels of parasitemia following P. berghei NK65 infection, although infected iNOS(-/-) mice presented early mortality. Inducible nitric oxide synthase deficiency led to increased leukocyte rolling and adhesion to the liver in iNOS(-/-) mice relative to the WT animals, as observed via intravital microscopy. Infected iNOS(-/-) mice also exhibited increased hepatic leukocyte migration and subsequent liver damage, which was associated with high serum levels of the cytokines TNF-α, IL-6 and IL-10. Our data suggest potential role for the iNOS enzyme as a regulator of hepatic inflammatory response induced by P. berghei NK65-infection, and its absence leads to exacerbated inflammation and sequential associated-hepatic damage in the animals.