Abstract
An increase in abundance and activity of N‐methyl D‐aspartate receptors (NMDAR) was previously reported for red blood cells (RBCs) of sickle cell disease (SCD) patients. Increased Ca2+ uptake through the receptor supported dehydration and RBC damage. In a pilot phase IIa‐b clinical trial MemSID, memantine, a blocker of NMDAR, was used for treatment of four patients for 12 months. Two more patients that have enrolled into the study did not finish it. One of them had psychotic event following the involuntary overdose of the drug, whereas the other had vertigo and could not comply to the trial visits schedule. Acute and durable responses of RBCs of SCD patients to daily oral administration of memantine were monitored. Markers of RBC turnover, changes in cell density, and alterations in ion handling and RBC morphology were assessed. Acute transient shifts in intracellular Ca2+, volume and density, and reduction in plasma lactate dehydrogenate activity were observed already within the first month of treatment. Durable effects of memantine included (a) decrease in reticulocyte counts, (b) reduction in reticulocyte hemoglobinization, (c) advanced membrane maturation and its stabilization as follows from reduction in the number of NMDAR per cell and reduction in hemolysis, and (iv) rehydration and decrease in K+ leakage from patients’ RBC. Memantine therapy resulted in reduction in number of cells with sickle morphology that was sustained at least over 2 months after therapy was stopped indicating an improvement in RBC longevity.
Highlights
Sickle cell disease (SCD) is recognized by the World Health Organization as a featured global mortality burden [1]
Some sickle cell disease (SCD) patients remain refractive to HU treatment, the others may suffer from a number of side effects [9]
Monoclonal anti-P-selectin antibody Crizanlizumab targets vaso-occlusion [12], whereas Voxelotor increases O2 affinity of hemoglobin S (HbS) interfering with its aggregation [13]
Summary
Sickle cell disease (SCD) is recognized by the World Health Organization as a featured global mortality burden [1] The cause of this disease is a point mutation in the β globin chain making the deoxygenated form of hemoglobin S (HbS) poorly soluble and prone to form rod-shape complexes that gives the cells famous “sickle” or “holy leaf” morphology, damages the membrane, and makes RBCs of SCD patients stiff and short-lived [2,3]. Deoxygenation, dehydration, and inflammation trigger HbS aggregation, red blood cell (RBC) membrane damage, and result in production of terminally sickled, highly adherent and fragile cells. This condition is associated with hemolysis, vaso-occlusive crises (VOCs) and pain episodes, and requires hospitalization, analgesics, and blood transfusions [4,5]. Several other drugs have been tested, some of which failed, the others being at different stages of testing in clinical trials [10]
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