Flupirtine and retigabine prevent l -glutamate toxicity in rat pheochromocytoma PC 12 cells

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 μM) 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 μM) 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

Flupirtine and retigabine prevent l -glutamate toxicity in rat pheochromocytoma PC 12 cells

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Publisher
Elsevier
Copyright
Copyright © 2000 Elsevier Science B.V.
ISSN
0014-2999
D.O.I.
10.1016/S0014-2999(00)00397-6
Publisher site
See Article on Publisher Site

Abstract

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 μM) 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 μM) 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.

Journal

European Journal of PharmacologyElsevier

Published: Jul 21, 2000

References

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