Abstract:
The biochemical and molecular events defining the precise role of oxidative stress in the inactivation of the cerebral electrogenic transmembrane sodium-potassium transporter (sodium pump) in radical-induced neurodegenerative diseases is complex and yet to be fully elucidated and thus still open. The present study sought to investigate the influence of different thiols (mono and dithiols), vitamin E and malondialdehyde (MDA) on the activity of the sodium pump in Fe2+-mediated in vitro oxidative stress model. The results show that Fe2+ inhibited the activity of the sodium pump in a concentration-dependent manner and this effect was accompanied by a biphasic generation of aldehydic products of lipid peroxidation. Furthermore, Fe2+ inhibited the activity of the pump irrespective of the exposed substrate [adenosine triphosphate (ATP) or cationic (Na+ or K+)] binding sites. However, while vitamin E prevented lipid peroxidation but not inhibition of the pump’s activity, conversely, dithiothreitol (DTT) and cysteine (CYS) prevented both Fe2+-mediated inhibition of the pump’s activity and lipid peroxidation, whereas glutathione (GSH) neither prevented the inhibitory effect of Fe2+ on the pump’s activity nor lipid peroxidation. In addition, irrespective of the exposed substrate binding sites, DTT reversed the Fe2+-induced inhibition of the pump’s activity, while CYS and GSH did not. Finally, malondialdehyde 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 direct Fe2+-mediated oxidation of the catalytically essential thiols of the enzyme located at, or near its ATP and cationic binding sites. However, during severe progression of such diseases; 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.
