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

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 D 1 ) neurons. hNT neurons were induced to apoptosis applying glutamate (Glu; at concentrations ≥ 1 mM) or NMDA (≥ 1 mM). During Glu/NMDA-mediated apoptosis the levels of the intracellular anti-apoptotic agents Bcl-2 and glutathione dropped by more than 50%. Flupirtine completely abolished this reduction of Bcl-2 and glutathione level at a concentration of 10 μM. In the presence of 3 μM flupirtine a > 6-fold increase of the Bcl-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 Bcl-2 and glutathione. Neuronal cell death by Glu or NMDA in vitro can be overcome applying the drug flupirtine which is in clinical use.