RESUMO
Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.
Assuntos
Acetilcisteína , Antioxidantes , Suplementos Nutricionais , Licopeno , Malária , Parasitemia , Plasmodium berghei , Animais , Licopeno/uso terapêutico , Licopeno/administração & dosagem , Licopeno/farmacologia , Parasitemia/tratamento farmacológico , Camundongos , Malária/tratamento farmacológico , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Acetilcisteína/farmacologia , Plasmodium berghei/efeitos dos fármacos , Antioxidantes/uso terapêutico , Antioxidantes/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Carotenoides/uso terapêutico , Carotenoides/administração & dosagem , Masculino , Modelos Animais de Doenças , Distribuição AleatóriaRESUMO
Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética , Animais , Antimaláricos/toxicidade , Domínio Catalítico , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Feminino , Hemólise/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/química , Macrófagos Peritoneais/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/enzimologia , Estrutura Quaternária de Proteína , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Relação Estrutura-Atividade , Triazóis/toxicidadeRESUMO
BACKGROUND: In vitro and in vivo testing of new technology was performed to evaluate the antiplasmodial activity of Photonic Multiphase Modulators (PMM) in cultures and in mice previously infected with Plasmodium falciparum and Plasmodium berghei parasites. METHODS: Cultures of P. falciparum infected-erythrocytes were exposed overnight to two generations of different APSE™ and BioPhoton-X™ PMM (C#1, R#1, R#2, D8 and D9). Growth of parasites was determined through flow cytometry or microscopy. Mice of the strain C57BL/6 were infected and treated with water exposed to second-generation APSE™ and BioPhoton-X™ PMM plus one previously untested first-generation PMM (AGN10). Parasitemia and weight loss were monitored throughout the infection until death or point of euthanasia was reached. After death, necropsy was performed on all animals and the number of days each survived was recorded. RESULTS: In vitro and in vivo testing using different APSE™- and BioPhoton-X™-designed PMM revealed an effect of D8 in lowering the growth of the parasite in vitro, while the best effect in mice was observed with D9 PMM, with a reduced weight loss and an increase in survival, although the results in lowering the parasitemia were inconclusive. D9 PMM did not generate ROS in vitro. CONCLUSIONS: APSE™ and BioPhoton-X™ optic circuit technologies can affect the growth of parasites and show protective effects in mice drinking from water treated with their PMM.
Assuntos
Antimaláricos/química , Água/química , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Eritrócitos/parasitologia , Malária/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óptica e Fotônica/métodos , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Different strategies for improvement of malaria control and elimination are based on the blockage of malaria parasite transmission to the mosquito vector. These strategies include the drugs that target the plasmodial sexual stages in humans and the early developmental stages inside mosquitoes. OBJECTIVES: Here we tested Malaria Box compounds in order to evaluate their activity against male and female gametocytes in Plasmodium berghei, mosquito infection in P. vivax and ookinete formation in both species. METHODS/FINDINGS: The membrane feeding assay and the development of ookinetes by a 24 h ex vivo culture and the ookinete yield per 1000 erythrocytes were used to test transmission-blocking potential of the Malaria Box compounds in P. vivax. For P. berghei we used flow cytometry to evaluate male and female gametocyte time course and fluorescence microscopy to check the ookinete development. The two species used in this study showed similar results concerning the compounds' activity against gametocytes and ookinetes, which were different from those in P. falciparum. In addition, from the eight Malaria Box compounds tested in both species, compounds MMV665830, MMV665878 and MMV665941 were selected as a hit compounds due the high inhibition observed. CONCLUSION: Our results showed that P. berghei is suitable as an initial screening system to test compounds against P. vivax.
Assuntos
Malária Vivax/prevenção & controle , Mosquitos Vetores/parasitologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Animais , Malária Vivax/tratamento farmacológico , Malária Vivax/transmissãoRESUMO
The present study aimed to evaluate the effects of dexamethasone on the redox status, parasitemia evolution, and survival rate of Plasmodium berghei-infected mice. Two-hundred and twenty-five mice were infected with Plasmodium berghei and subjected to stimulation or inhibition of NO synthesis. The stimulation of NO synthesis was performed through the administration of L-arginine, while its inhibition was made by the administration of dexamethasone. Inducible NO synthase (iNOS) inhibition by dexamethasone promoted an increase in the survival rate of P. berghei-infected mice, and the data suggested the participation of oxidative stress in the brain as a result of plasmodial infection, as well as the inhibition of brain NO synthesis, which promoted the survival rate of almost 90% of the animals until the 15th day of infection, with possible direct interference of ischemia and reperfusion syndrome, as seen by increased levels of uric acid. Inhibition of brain iNOS by dexamethasone caused a decrease in parasitemia and increased the survival rate of infected animals, suggesting that NO synthesis may stimulate a series of compensatory redox effects that, if overstimulated, may be responsible for the onset of severe forms of malaria.
Assuntos
Arginina/farmacologia , Dexametasona/farmacologia , Inibidores Enzimáticos/farmacologia , Malária/tratamento farmacológico , Óxido Nítrico/metabolismo , Parasitemia/tratamento farmacológico , Animais , Masculino , Camundongos , Plasmodium berghei/efeitos dos fármacosRESUMO
BACKGROUND: Malaria is a parasitic disease that compromises the human host. Currently, control of the Plasmodium falciparum burden is centered on artemisinin-based combination therapies. However, decreased sensitivity to artemisinin and derivatives has been reported, therefore it is important to identify new therapeutic strategies. METHOD: We used human erythrocytes infected with P. falciparum and experimental cerebral malaria (ECM) animal model to assess the potential antimalarial effect of eugenol, a component of clove bud essential oil. RESULTS: Plasmodium falciparum cultures treated with increasing concentrations of eugenol reduced parasitemia in a dose-dependent manner, with IC50 of 532.42 ± 29.55 µM. This effect seems to be irreversible and maintained even in the presence of high parasitemia. The prominent effect of eugenol was detected in the evolution from schizont to ring forms, inducing important morphological changes, indicating a disruption in the development of the erythrocytic cycle. Aberrant structural modification was observed by electron microscopy, showing the separation of the two nuclear membrane leaflets as well as other subcellular membranes, such as from the digestive vacuole. Importantly, in vivo studies using ECM revealed a reduction in blood parasitemia and cerebral edema when mice were treated for 6 consecutive days upon infection. CONCLUSIONS: These data suggest a potential effect of eugenol against Plasmodium sp. with an impact on cerebral malaria. GENERAL SIGNIFICANCE: Our results provide a rational basis for the use of eugenol in therapeutic strategies to the treatment of malaria.
Assuntos
Antimaláricos/farmacologia , Edema Encefálico/tratamento farmacológico , Eugenol/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Cerebral/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/parasitologia , Edema Encefálico/parasitologia , Modelos Animais de Doenças , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Humanos , Concentração Inibidora 50 , Estágios do Ciclo de Vida/fisiologia , Malária Cerebral/parasitologia , Malária Falciparum/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/patogenicidadeRESUMO
Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ-gold(I) hybrid molecule affects essential parasite targets, it inhibits ß-hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ-gold(I) hybrid displayed an excellent inâ vitro antimalarial activity against the blood-stage of Plasmodium falciparum and liver-stage of Plasmodium berghei and efficacy inâ vivo against P. berghei, thereby demonstrating its multiple-stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.
Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Ouro/farmacologia , Primaquina/farmacologia , Antimaláricos/química , Cloroquina/química , Relação Dose-Resposta a Droga , Ouro/química , Humanos , Malária/tratamento farmacológico , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Primaquina/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND Different strategies for improvement of malaria control and elimination are based on the blockage of malaria parasite transmission to the mosquito vector. These strategies include the drugs that target the plasmodial sexual stages in humans and the early developmental stages inside mosquitoes. OBJECTIVES Here we tested Malaria Box compounds in order to evaluate their activity against male and female gametocytes in Plasmodium berghei, mosquito infection in P. vivax and ookinete formation in both species. METHODS/FINDINGS The membrane feeding assay and the development of ookinetes by a 24 h ex vivo culture and the ookinete yield per 1000 erythrocytes were used to test transmission-blocking potential of the Malaria Box compounds in P. vivax. For P. berghei we used flow cytometry to evaluate male and female gametocyte time course and fluorescence microscopy to check the ookinete development. The two species used in this study showed similar results concerning the compounds' activity against gametocytes and ookinetes, which were different from those in P. falciparum. In addition, from the eight Malaria Box compounds tested in both species, compounds MMV665830, MMV665878 and MMV665941 were selected as a hit compounds due the high inhibition observed. CONCLUSION Our results showed that P. berghei is suitable as an initial screening system to test compounds against P. vivax.
Assuntos
Animais , Plasmodium berghei/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Malária Vivax/prevenção & controle , Mosquitos Vetores/parasitologia , Malária Vivax/tratamento farmacológico , Malária Vivax/transmissãoRESUMO
BACKGROUND & OBJECTIVES: In Colombian Amazonia, Uitoto indigenous people use a preparation of Curarea toxicofera (Menispermaceae) to prevent and treat malaria. To open the way for the production of a standardized herbal remedy, we compared the activity of the traditional preparation with laboratory preparations. METHODS: People were interviewed on their mode of use and preparation of what is considered the best remedy against fevers in this area. The herbal remedy was prepared according to the healer's recommendations. The plant was also submitted to continuous distillation and percolation extraction. The preparations were then tested against Plasmodium falciparum, in vitro. Traditional preparation and extract obtained by percolation were tested on Plasmodium berghei infected mice. Chemical profiles were also explored by thin-layer chromatography. RESULTS: Yields of extraction were around 7% in the preparations (percolation was the most efficient). The phytochemical profile showed a mix of steroids, flavonoids and alkaloids qualitatively similar in all preparations. In vitro, the extracts showed inhibitory concentration 50 <10µg/mL: the traditional preparation was almost three times less active than laboratory preparations. In vivo, percolation was also more active than traditional preparation, inhibiting 78% of the parasite growth at 400mg/kg/day by oral route. INTERPRETATION & CONCLUSION: Pharmacological activities suggest that both the original remedy (prepared according to traditional pharmacopeia) and the extracts obtained by percolation extraction exhibit relevant antiparasitic activity. C. toxicofera should therefore be considered for the elaboration of an improved traditional medicine by implementing toxicological studies and carefully following quality control guidelines for its preparation.
Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Menispermaceae/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Animais , Colômbia , Humanos , Malária/parasitologia , Medicina Tradicional , Camundongos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Plantas Medicinais , Plasmodium falciparum/efeitos dos fármacosRESUMO
Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.