A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment

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.

Trends in the Development of Diagnostic Tools for Red Blood Cell-Related Diseases and Anemias

“…It is a microfluidic device that can challenge red blood cells chemically or with functional surfaces, while red blood cells are microscopically observed. Although it is not yet on the market, it is under investigation in several hematologic laboratories within Europe and in a clinical trial testing the efficiency of Memantine for the treatment of sickle cell disease (Makhro et al, 2020).…”

N-Methyl-D-Aspartate Receptors in Hematopoietic Cells: What Have We Learned?

“…There are no reports of abnormal RBC counts in patients with Alzheimer's disease taking memantine to protect the brain from glutamatergic excitotoxicity (Kavirajan, 2009). One pilot clinical trial was performed at the University Hospital Zurich, in which patients with sickle cell disease received memantine over a year (Makhro et al, 2020;trial identifier NCT02615847), and the other is currently ongoing (trial identifier NCT03247218). These trials provide an opportunity to explore long-term effects of NMDAR inhibition on RBC and platelet production, and cell properties in humans.…”

Lysophosphatidic Acid-Activated Calcium Signaling Is Elevated in Red Cells from Sickle Cell Disease Patients

“…One direct Ca 2+ entry pathway, which is elevated in SCD RBCs, was shown to be the NMDA receptor [ 12 , 13 ]. A recent clinical trial with memantine, an antagonist of the NMDA receptor, showed promising results [ 14 , 15 ]. Here we provide evidence for a further player, lysophosphatidic acid (LPA), that activates a signaling cascade, leading to increased intracellular Ca 2+ and this Ca 2+ entry pathway is upregulated in RBCs of SCD patients.…”