Abstract
Memantine is approved for the treatment of advanced Alzheimer's disease (AD) and reduces glutamate-mediated neuronal excitotoxicity by antagonism of N-methyl-D-aspartate receptors. In the pathophysiology of AD immune responses deviate and infectious side effects are observed during memantine therapy. However, the particular effects of memantine on human T lymphocytes are unresolved. Here, we provide evidence that memantine blocks Kv1.3 potassium channels, inhibits CD3-antibody- and alloantigen-induced proliferation and suppresses chemokine-induced migration of peripheral blood T cells of healthy donors. Concurrent with the in vitro data, CD4+ T cells from AD patients receiving therapeutic doses of memantine show a transient decline of Kv1.3 channel activity and a long-lasting reduced proliferative response to alloantigens in mixed lymphocyte reactions. Furthermore, memantine treatment provokes a profound depletion of peripheral blood memory CD45RO+ CD4+ T cells. Thus, standard doses of memantine profoundly reduce T cell responses in treated patients through blockade of Kv1.3 channels. This may normalize deviant immunopathology in AD and contribute to the beneficial effects of memantine, but may also account for the enhanced infection rate.
Highlights
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Axura®, Ebixa®, Namenda®) is approved for the treatment of moderate to severe Alzheimers disease (AD)
T cell proliferation induced by amyloid beta (A-beta) or alloantigens in mixed lymphocyte reactions (MLRs) and transendothelial migration of T cells via the blood brain barrier are enhanced in AD patients compared to age-matched controls [7,8,9,10,11,12,13]
To assess the impact of memantine on the proliferation of human T cells, DNA synthesis of CD3+ cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors was evaluated by 3[H]Thymidine incorporation in the presence or absence of memantine
Summary
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Axura®, Ebixa®, Namenda®) is approved for the treatment of moderate to severe Alzheimers disease (AD). Undesired neuronal side effects include somnolence, confusion and headache [3, 4]. NMDA receptors seem to be expressed on non-neuronal cells, www.impactjournals.com/oncotarget including human peripheral blood lymphocytes (PBLs) and leukemic Jurkat T cells [15,16,17,18,19,20]. Memantine cross-targets other ligand-gated ion channels like Kir2.1 channels expressed on macrophages and microglia [21] and suppresses murine lymphocyte function through crossinhibition of Kv1.3 and KCa3.1 potassium channels [22, 23]. The particular effects of memantine on human T cells, are unresolved
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