S. Perovic et al., 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/, European journal of pharmacology, 317(1), 1996, pp. 157-164
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.