monensin and Hemolysis

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.

Topics: Antimalarials; Cell Line; Erythrocytes; Hemolysis; Humans; Inhibitory Concentration 50; Ionophores; Molecular Structure; Monensin; Nigericin; Plasmodium berghei; Plasmodium falciparum; Pyrans

PLGA nanoparticles loaded with monensin (carboxylic ionophore) were prepared by emulsion solvent evaporation method using PLGA of molecular weight (Mw.) 19000 and 110000 Da. The nanoparticles were characterized by applying dynamic light scattering (DLS), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). Negatively charged and spherical smooth surfaced nanoparticles of size range between 147-167 nm were obtained. The nanoparticles of monensin-PLGA showed no chemical interaction between monensin and the polymer molecules. The release kinetics in vitro studies exhibited biphasic release profile characterized by an initial fast release followed by a slower release. The antimalarial efficacy of monensin-PLGA nanoparticles was also examined. Monensin loaded in nanoparticles was 10-fold more effective in inhibiting the growth of P. falciparum in vitro as compared to free monensin. The antimalarial efficacy of monensin-PLGA nanoparticles was significantly dependent on the Mw. of the polymer.

Topics: Antimalarials; Calorimetry, Differential Scanning; Cells, Cultured; Emulsions; Erythrocytes; Hemolysis; Humans; Lactic Acid; Molecular Weight; Monensin; Nanoparticles; Particle Size; Plasmodium falciparum; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Spectroscopy, Fourier Transform Infrared

Mean cell hemoglobin concentration (MCHC) is thought to have an important influence in sickle cell disease, both through the strong dependence of sickling rates on hemoglobin S concentration, and through the profoundly limiting effect of high MCHC on the rheologic competence of oxygenated, irreversibly sickled cells (ISC). Recent studies have tested the ability of antidiuretic hormone to reduce sickle cell MCHC by reducing plasma sodium (Na) and osmolality. An alternative means of reducing MCHC is to elevate intracellular cation content, rather than to depress extracellular cation concentration. In an effort to do this, we have treated sickle cells with Monensin, an antibiotic that selectively enhances membrane Na permeability. At submicromolar concentrations, Monensin substantially reduced the MCHC of whole sickle blood and isolated ISC, causing an improvement in cell deformability. Monensin's effectiveness in producing a controlled increase in erythrocyte water content suggests that agents that selectively increase membrane Na permeability could be therapeutically useful.

Topics: Anemia, Sickle Cell; Centrifugation, Density Gradient; Erythrocytes, Abnormal; Furans; Hemoglobin C; Hemoglobin, Sickle; Hemolysis; Humans; Hydrogen-Ion Concentration; Ionophores; Models, Biological; Monensin; Osmolar Concentration; Potassium; Sodium; Stimulation, Chemical; Water-Electrolyte Balance