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.
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.
Perovic
S
S
Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität, Mainz, Germany.
Pialoglou
P
P
Schröder
H C
HC
Pergande
G
G
Müller
W E
WE
D000631:Aminopyridines / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D053938:DNA Fragmentation; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
D000631:Aminopyridines; D018712:Analgesics, Non-Narcotic; D018690:Excitatory Amino Acid Agonists; D019253:Proto-Oncogene Proteins c-bcl-2; D018698:Glutamic Acid; D016202:N-Methylaspartate; D005978:Glutathione; C034161:flupirtine