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) an d the related compound N-(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid, ethyl ester) (retigabine) (Desaza-flupirtine) on the toxicity of L-gl utamate and L-3,4-dihydroxyphenylalanine (L-DOPA) in rat pheochromocytoma P C 12 cells in vitro. Both drugs (10 mu M) markedly decreased nonreceptor-me diated necrotic cell death in PC 12 cultures treated with L-glutamate (10 m M) for 72 h. In contrast, apoptosis induced by L-DOPA (250 I-LM) after 48 h was not affected by either substance. While L-DOPA elicited massive genera tion of reactive oxygen intermediates, L-glutamate-induced eel death was ac companied by only slightly increased levels of reactive oxygen intermediate s. Flupirtine and rerigabine exerted anti-oxidative effects in PC 12 cultur es independent of their ability to prevent cell death. Further examination of the protective action of flupirtine and retigabine against L-glutamate t oxicity showed that it had no influence on monoamine oxidase (monoamine: ox ygen oxidoreductase (deaminating), EC 1.4.3.4., MAO) activity. Thus, flupir tine and retigabine provided protection against cystine deprivation and L-g lutamate toxicity but did not protect against L-glutamate under cystine-fre e conditions indicating that both compounds are sufficiently effective to c ompensate the oxidative stress elicited by cystine deprivation but not exce ssive activity of monoamine oxidase after L-glutamate treatment. (C) 2000 E lsevier Science B.V. All rights reserved.