Diphenyl diselenide and analogs are substrates of cerebral rat thioredoxin reductase: A pathway for their neuroprotective effects

Abstract

Thioredoxin reductase (TrxR) isoforms play important roles in cell physiology, protecting cells against oxidative processes. In addition to its endogenous substrates (Trx isoforms), hepatic TrxR can reduce organic selenium compounds such as ebselen and diphenyl diselenide to their selenol intermediates, which can be involved in their hepatoprotective properties. Taking this into account, the aim of the present study was to evaluate the hypothesis that ebselen, diphenyl diselenide and its analogs (4,4'-bistrifluoromethyldiphenyl diselenide, 4,4'-bismethoxydiphenyl diselenide, 4.4'-biscarboxy-diphenyl diselenide, 4,4'-bischlorodiphenyl diselenide, 2,4,6,2',4',6'-hexamethyldiphenyl diselenide) could be substrates of rat brain TrxR. In the presence of partially purified rat brain TrxR, diphenyl diselenide, bismethoxydiphenyl diselenide and bischlorodiphenyl diselenide (at 10, 15 and 20μM) stimulated NADPH oxidation, indicating that they are substrates of brain TrxR. In contrast, ebselen and bistrifluoromethyldiphenyl diselenide, that have been previously demonstrated to be substrate of hepatic TrxR, were not reduced by rat brain TrxR. The results presented here suggest that diphenyl diselenide can exert neuroprotective effects by mimicking glutathione peroxidase activity and also via its reduction by TrxR. However, ebselen was not reduced by brain TrxR, indicating that the neuroprotective properties of this compound is possibly mediate by its glutathione peroxidase-like activity.

Could Selenium Administration Alleviate the Disturbances of Blood Parameters Caused by Lithium Administration in Rats?

“…As long-term lithium therapy is used in the cure of this disease, the question of the influence of lithium on oxidative processes is an issue of great importance. The organisms developed a complex system of defence against oxidative stress which includes numerous substances, among other things antioxidant enzymes, namely superoxide dismutase, glutathione peroxidase and catalase [14, 40, 42, 43]. In this pilotage study, we investigated two of them: superoxide dismutase and glutathione peroxidase.…”

“…Selenium, an essential trace element, is necessary to correct an organism’s functions [14, 15]. Being a constituent of one of the main antioxidative enzymes—glutathione peroxidase—selenium is considered to be an antioxidant [14].…”

“…Being a constituent of one of the main antioxidative enzymes—glutathione peroxidase—selenium is considered to be an antioxidant [14]. Research has indicated that bipolar and neurological disorders like epilepsy are associated with oxidative stress, and selenium compounds can display neuroprotective effects by different mechanisms, with the involvement of selenoproteins [14–19]. Selenium supplementation has been suggested to be beneficial in psychiatric disorders [20].…”

Diphenyl Diselenide Modulates Gene Expression of Antioxidant Enzymes in the Cerebral Cortex, Hippocampus and Striatum of Female Hypothyroid Rats

“…Diphenyl diselenide has a wide spectrum of antioxidant effects, such as the well-documented GPx-like activity [52,57] and the recent findings showing that the compound increases cellular GPx expression, possibly via Nrf-2 transcription factor activation [68,76]. In addition, diphenyl diselenide can be reduced by cerebral TrxR and increase the intracellular pool of GSH by stimulating the γ-glutamyl cysteine synthetase enzyme activity [58,68,83]. …”

Organochalcogens Inhibit Mitochondrial Complexes I and II in Rat Brain: Possible Implications for Neurotoxicity

“…The documented antioxidant activity of the organochalchogens has been partially attributed to their glutathione- and thioredoxin reductase-like activities (de Freitas and Rocha 2011; Maiorino et al 1988; Sausen de Freitas et al 2010; Sies 1993; Sies 1995; Zhao and Holmgren 2002; Zhao et al 2002). In order to reduce peroxides, the selenium containing compounds must first form selenol/selenolate intermediates, a reaction which is catalyzed via reduction of the Se moiety by various thiols (Nogueira and Rocha 2010; Nogueira et al 2004; Wendel et al 1984).…”