Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness

// Theresa Lowinus 1 , Tanima Bose 2, 6 , Stefan Busse 3 , Mandy Busse 4 , Dirk Reinhold 1 , Burkhart Schraven 1, 5 , Ursula H.H. Bommhardt 1 1 Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany 2 Molecular Physiology, Leibniz Institute for Neurobiology, Magdeburg, Germany 3 Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany 4 Department of Pediatric Pulmonology & Allergology, Medical University of Hannover, Hannover, Germany 5 Department of Immune Control, Helmholtz Centre for Infection Research, Braunschweig, Germany 6 Current address: Lee Kong Chian School of Medicine, Singapore Correspondence to: Ursula H.H. Bommhardt, email: Ursula.Bommhardt@med.ovgu.de Keywords: human T cells, memantine, K v 1.3 potassium channel, NMDA receptor antagonist, Alzheimer´s disease Received: February 04, 2016 Accepted: July 09, 2016 Published: July 22, 2016 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 K v 1.3 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 K v 1.3 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 K v 1.3 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.