Flupirtine increases the levels of glutathione and Bc1-2 in hNT (human Ntera/D1) neurons: mode of action of the drug-mediated anti-apoptotic effect

European Journal of Pharmacology
S PerovicW E Müller

Abstract

Flupirtine is a triaminopyridine analogue which has been successfully applied in clinics as a non-opiate analgesic drug. Previously we described that flupirtine acts like an N-methyl-D-aspartate (NMDA) receptor antagonist in neuronal cells both in vitro and in vivo. Here we show that flupirtine displays its anti-apoptotic effect also in hNT (human Ntera/D1) neurons. hNT neurons were induced to apoptosis applying glutamate (Glu; at concentrations > or = 1 mM) or NMDA (> or = 1 mM). During Glu/NMDA-mediated apoptosis the levels of the intracellular anti-apoptotic agents Bc1-2 and glutathione dropped by more than 50%. Flupirtine completely abolished this reduction of Bc1-2 and glutathione level at a concentration of 10 microM. In the presence of 3 microM flupirtine a > 6-fold increase of the Bc1-2 (B-cell leukemia/lymphoma-2) level was observed in hNT neurons. At the same concentration, the intracellular level of glutathione increased to 200%. We conclude that the Glu/NMDA-mediated neuronal cell death in vitro is controlled at least partially by Bc1-2 and glutathione. Neuronal cell death by Glu or NMDA in vitro can be overcome applying the drug flupirtine which is in clinical use.

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Citations

Jun 22, 2006·Neurotoxicity Research·V Pedersen, W J Schmidt
Apr 28, 2004·The International Journal of Biochemistry & Cell Biology·Maria Giuseppina MontiMaria Stella Moruzzi
Nov 24, 1998·Biochemical Pharmacology·M GassenM B Youdim
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Mar 27, 2003·Progress in Neuro-psychopharmacology & Biological Psychiatry·Peter C Waldmeier
Apr 9, 2015·Frontiers in Cellular Neuroscience·Aristeidis A KritisTheofanis D Vavilis
Sep 15, 2004·Brain Research. Molecular Brain Research·William R SchelmanJames A Weyhenmeyer
Aug 13, 2010·Medical Hypotheses·Burak TatliMeral Ozmen
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Mar 28, 2012·Expert Review of Neurotherapeutics·Burak TatliMeral Ozmen
May 6, 1999·Nature Medicine·A SchneiderM Schwaninger

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