Possible involvement of membrane lipids peroxidation and oxidation of catalytically essential thiols of the cerebral transmembrane sodium pump as component mechanisms of iron-mediated oxidative stress-linked dysfunction of the pump's activity

●Fe2+ evoked lipid peroxidation (LPO) and inhibition of sodium pump (SP) in rat brain.●However, dithiothreitol prevented both Fe2+-mediated LPO and inhibition of SP.●Conversely, vitamin E prevented only Fe2+-mediated LPO but not inhibition of SP.●Thus Fe2+ mediated inactivation of SP likely by oxidizing the essential thiol on SP.●However, malondialdehyde inhibited SP by a mechanism not related to thiol oxidation.

The precise molecular events defining the complex role of oxidative stress in the inactivation of the cerebral sodium pump in radical-induced neurodegenerative diseases is yet to be fully clarified and thus still open. Herein we investigated the modulation of the activity of the cerebral transmembrane electrogenic enzyme in Fe2+-mediated in vitro oxidative stress model. The results show that Fe2+ inhibited the transmembrane enzyme in a concentration dependent manner and this effect was accompanied by a biphasic generation of aldehydic product of lipid peroxidation. While dithiothreitol prevented both Fe2+ inhibitory effect on the pump and lipid peroxidation, vitamin E prevented only lipid peroxidation but not inhibition of the pump. Besides, malondialdehyde (MDA) inhibited the pump by a mechanism not related to oxidation of its critical thiols. Apparently, the low activity of the pump in degenerative diseases mediated by Fe2+ may involve complex multi-component mechanisms which may partly involve an initial oxidation of the critical thiols of the enzyme directly mediated by Fe2+ and during severe progression of such diseases; aldehydic products of lipid peroxidation such as MDA may further exacerbate this inhibitory effect by a mechanism that is likely not related to the oxidation of the catalytically essential thiols of the ouabain-sensitive cerebral electrogenic pump.

Influence of vitamin E, dithiothreitol on Fe2+ -mediated dysfunction of sodium pump in rat brain.Figure optionsDownload as PowerPoint slide