Drugs for preventing red blood cell dehydration in people with sickle cell disease

Nagalla, Srikanth; Ballas, Samir K.

doi:10.1002/14651858.cd003426.pub4

Cited by 17 publications

(16 citation statements)

References 69 publications

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“…Indeed, a clinical trial with senicapoc has already been established for the treatment of disorders of secondary erythrocyte hydration, such as sickle cell disease, demonstrating increased Hb and reduced markers of hemolysis in treated patients. 82,83 …”

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New insights on hereditary erythrocyte membrane defects

et al. 2016

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© Ferrata Storti Foundationmary role in the removal of aged RBCs. In order to perform these journeys RBCs must possess and maintain a significant deformability. The main author of this property is certainly the membrane, that ensures both mechanical stability and deformability. After the first proposed model of the RBC membrane skeleton 36 years ago, 1 containing the core elements of the modern model, many additional proteins have been discovered during the intervening decades, and their structures and interactions have been defined. RBC membrane structure has been extensively covered by excellent reviews.2,3 Herein we summarize the main concepts. RBC membrane is composed by a fluid double layer of lipids in which approximately 20 major proteins and at least 850 minor ones are embedded. 4 The membrane is attached to an intracellular cytoskeleton by protein-protein and lipid-protein interactions that confer the erythrocyte shape, stability and deformability. The transmembrane proteins have mainly a transporter function. However, several of these also have a structural function, usually performed by an intracytoplasmic domain interacting with cytoskeletal proteins.The lipid bilayer acts as a barrier for the retention of cations and anions within the red cells, while it allows water molecules to pass through freely. Human erythrocytes have high intracellular K + and low intracellular Na + contents when compared with the corresponding ion concentrations in the plasma. The maintenance of this cation gradient between the cell and its environment involves a passive outward movement of K + , which is pumped back by the action of an ATP-dependent Na + /K + pump in exchange for Na+ ions. This protein belongs to a class of transmembrane proteins with a transport function (Figure 1). The third and more important component of the RBC membrane is the cytoskeleton, a protein network that laminates the inner surface of the membrane. Spectrin aand β-chains, proteins 4.1, or 4.1R, and actin are the main components of this skeleton, maintaining the biconcave shape of the RBC. These components are connected to each other in two protein complexes; ankyrin and protein 4.1 complex. The former is composed by band 3 tetramers, Rh, RhAG, CD47, glycophorin A and protein 4.2. Whereas the protein 4.1 complex is composed by band 3 dimers binding adducins a-and β-, glycophorin C, GLUT1 and stomatin (Figure 1). The ends of spectrin tetramers converge toward a protein 4.1 complex (junctional complex). Electron microscopy (EM) shows that this latter links the tail of six spectrin tetramers, forming a pseudo-hexagonal arrangement. 5Spectrin tetramers include anion transporters (band 3 or chloride/bicarbonate exchange). The capability of these transporters to form aggregates could define the half-life of RBCs, causing antibody binding and removal by the spleen. Defects that interrupt this vertical structure (spectrin-actin interaction) underlie the biochemical and molecular basis of hereditary spherocytosis (HS), whereas defects in horizo...

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New insights on hereditary erythrocyte membrane defects

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“…Such action could also be useful in rehydrating erythrocytes in pathological conditions such as sickle cell disease 30 .…”

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confidence: 99%

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2016

IJPSR

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Human erythrocytes were pre-incubated in vitro with paracetamol and then erythrocyte's rheological properties of deformability, osmotic fragility and aggregation were evaluated after being compromised by various means. Paracetamol (1, 2, 4mg/ml) significantly prevented the loss of deformability through 5m diameter pores of erythrocytes dehydrated with hypertonic buffer or with calcium ionophore A23187 at 4 mg/ml. When the potassium ionophore valinomycin was used to induce cell dehydration, paracetamol (4mg/ml) also prevented partially the loss of deformability. Paracetamol (4mg/ml) also decreased significantly erythrocyte osmotic fragility induced by hypotonic saline, and prevented significantly the aggregation of erythrocytes induced by dextran 70. The antioxidant properties of paracetamol was studied by chemical assays and found to be as follows: total antioxidant capacity (88.9 µg AAE/mg), reducing power (A 0 at 700 nm= 1.0 compared to 3.0 for Vit. C), DPPH scavenging activity (IC 50 = 62.5 µg/ml compared to 5.8 for Vit. C), OH· scavenging activity (IC 50 = 40.2 µg/ml compared to <10 for catecholamin), iron chelating (IC 50 = 144.6 µg/ml compared to 17.3 for EDTA) and Paracetamol at 1, 2, 4, 5 mg/ml also prevented significantly lipid peroxidation in a concentration dependent manner of human erythrocytes incubated with H 2 O 2 . The observed rheological and anti-lipid-peroxidant effects of paracetamol could be explained by its antioxidant activity, thus protecting membrane integrity and deformability. The results suggest that paracetamol could have a rheologically useful role on erythrocytes, preventing dehydration, aggregation and lipid-peroxidation, that may contribute positively to its analgesic and antipyretic effects.

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“…Como hemos mencionado anteriormente, la relación RDW y anemia ha sido muy bien estudiada desde la década del sesenta [10][11][12][13][14] . Sin embargo, en el año 2007 se ha generado un punto de inflexión de relevancia clínica: el redescubrimiento de este parámetro como potencial biomarcador de riesgo cardiovascular 15 .…”

Section: Rdw Y Nuevo Paradigma En Enfermedades Cardiovascularesunclassified