title: Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness.
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.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Lowinus
authors.affiliation: Molecular Physiology, Leibniz Institute for Neurobiology, Magdeburg, Germany.|Current address: Lee Kong Chian School of Medicine, Singapore.
authors.forename: Tanima
authors.initials: T
authors.lastname: Bose
authors.affiliation: Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Busse
authors.affiliation: Department of Pediatric Pulmonology & Allergology, Medical University of Hannover, Hannover, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Busse
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.|Department of Immune Control, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Ursula H H
authors.initials: UH
authors.lastname: Bommhardt
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D051664:Kv1.3 Potassium Channel / Q000187:drug effects*; D008559:Memantine / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D051664:Kv1.3 Potassium Channel; D018696:Neuroprotective Agents; D008559:Memantine
keywords: Alzheimer´s disease; Kv1.3 potassium channel; NMDA receptor antagonist; human T cells; memantine