Flupirtine and retigabine prevent L-glutamate toxicity in rat pheochromocytoma PC 12 cells.
Flupirtine is an analgesic drug thought to have NMDA receptor antagonistic and antiapoptotic effects. We investigated the effects of Ethyl-2-amino-6-(4-(4-fluorbenzyl)amino)-pyridine-3-carbamamic+ ++ acid, maleate (flupirtine) and the related compound N-(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid, ethyl ester) (retigabine) (Desaza-flupirtine) on the toxicity of L-glutamate and L-3,4-dihydroxyphenylalanine (L-DOPA) in rat pheochromocytoma PC 12 cells in vitro. Both drugs (10 microM) markedly decreased nonreceptor-mediated necrotic cell death in PC 12 cultures treated with L-glutamate (10 mM) for 72 h. In contrast, apoptosis induced by L-DOPA (250 microM) after 48 h was not affected by either substance. While L-DOPA elicited massive generation of reactive oxygen intermediates, L-glutamate-induced cell death was accompanied by only slightly increased levels of reactive oxygen intermediates. Flupirtine and retigabine exerted anti-oxidative effects in PC 12 cultures independent of their ability to prevent cell death. Further examination of the protective action of flupirtine and retigabine against L-glutamate toxicity showed that it had no influence on monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), EC 1.4.3.4., MAO) activity. Thus, flupirtine and retigabine provided protection against cystine deprivation and L-glutamate toxicity but did not protect against L-glutamate under cystine-free conditions indicating that both compounds are sufficiently effective to compensate the oxidative stress elicited by cystine deprivation but not excessive activity of monoamine oxidase after L-glutamate treatment.
Seyfried
J
J
Department of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076, Tubingen, Germany. j.seyfried@uni-bonn.de
Evert
B O
BO
Rundfeldt
C
C
Schulz
J B
JB
Kovar
K A
KA
Klockgether
T
T
Wüllner
U
U
D000631:Aminopyridines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003010:Clorgyline / Q000494:pharmacology; D003470:Culture Media; D003553:Cystine / Q000172:deficiency / Q000378:metabolism / Q000493:pharmacokinetics; D015259:Dopamine Agents / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016716:PC12 Cells; D010655:Phenylenediamines / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology
D000631:Aminopyridines; D000700:Analgesics; D000928:Antidepressive Agents; D002219:Carbamates; D003470:Culture Media; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D008996:Monoamine Oxidase Inhibitors; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C101866:ezogabine; D018698:Glutamic Acid; D007980:Levodopa; D003553:Cystine; D008995:Monoamine Oxidase; D005978:Glutathione; D003010:Clorgyline; C034161:flupirtine