FLUPIRTINE INCREASES THE LEVELS OF GLUTATHIONE AND BCL-2 IN HNT (HUMAN NTERA D1) NEURONS - MODE OF ACTION OF THE DRUG-MEDIATED ANTI-APOPTOTIC EFFECT/

Flupirtine is a triaminopyridine analogue which has been successfully applied in clinics as a non-opiate analgesic drug. Previously we descr ibed that flupirtine acts like an N-methyl-o-aspartate (NMDA) receptor antagonist in neuronal cells both in vitro and in vive. Here we show that flupirtine displays its anti-apoptotic effect also in hNT (human Ntera/D1) neurons. hNT neurons were induced to apoptosis applying glut amate (Glu; at concentrations greater than or equal to 1 mM) or NMDA ( greater than or equal to 1 mM). During Glu/NMDA-mediated apoptosis the levels of the intracellular anti-apoptotic agents Bcl-2 and glutathio ne dropped by mon than 50%. Flupirtine completely abolished this reduc tion of Bcl-2 and glutathione level at a concentration of 10 mu M. In the presence of 3 mu M flupirtine a > 6-fold increase of the Bcl-2 (B- cell leukemia/lymphoma-2) level was observed in hNT neurons. At the sa me concentration, the intracellular level of glutathione increased to 200%. We conclude that the Glu/NMDA-mediated neuronal cell death in vi tro is controlled at least partially by Bcl-2 and glutathione. Neurona l cell death by Glu or NMDA in vitro can be overcome applying the drug flupirtine which is in clinical use.