The Pharmacology and Therapeutic Utility of Sodium Hydroselenide

Abstract

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe-/H2Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O2 consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H2O2), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed.

The Role of Selenium in Pathologies: An Updated Review

“…Endogenously generated H 2 Se is indirectly incorporated into a number of selenoproteins with an oxidoreductase function. The administration of H 2 Se proved to transiently inhibit the mitochondrial cytochrome C oxidase [ 23 , 24 ].…”

Emerging roles of ER-resident selenoproteins in brain physiology and physiopathology

“…Tat SelPep contains two Sec residues, crosses the mouse blood-brain barrier, and protects against ferroptosis and cell death by stimulating GPX4 expression after stroke [ 32 ]. These peptides may be more specific than selenium supplementation [ 181 ] or intravenous hydroselenide injection [ 182 ], with fewer side effects. A better understanding of their mechanism could lead to the development of useful therapeutic tools specifically targeting Ca 2+ handling proteins and protein quality control or degradation, similar to chaperone therapies [ 183 ].…”

Cysteine-Activated Small-Molecule H2Se Donors Inspired by Synthetic H2S Donors

“…Gasotransmitters (NO, CO, and H 2 S) are endogenously generated signaling molecules that are involved in many physiological and pathological processes. H 2 Se shares some characteristics with these gasotransmitters − and is recently suggested as the fourth member . Compared with its analogue H 2 S, H 2 Se is a better nucleophile and a more potent reductant .…”

“…H 2 Se can be enzymatically generated from organic Se compounds by selenocysteine β-lyase (SCLY) and methylselenol demethylase (MSDM), as well as from inorganic Se compounds by thioredoxin reductase (TrxR) and glutathione reductase (GR) . Endogenously generated H 2 Se is then converted to selenophosphate for downstream biosynthesis of selenoproteins , and other selenium-containing biomolecules in vivo. , Additionally, H 2 Se may be involved in signal transduction pathways and participate in many biochemical reactions. − ,− For example, H 2 Se can act as a redox-balance modulating agent by direct detoxification of reactive oxygen species (ROS) , or reduction of disulfide and sulfilimine bonds in proteins. , H 2 Se is an efficient ligand for metal–ion coordination and has been incorporated into some bioinorganic clusters. , Complementing the importance of H 2 Se in mammals, H 2 Se in bacteria (e.g., gut microbiota) and plants (e.g., grain crops) is also relevant to human health . Nevertheless, the physiological characteristics of H 2 Se and the molecular mechanisms by which H 2 Se may be involved still remain largely unclear and/or unexplored.…”

“…Inorganic selenite and selenate salts need to be reduced by endogenous antioxidants to the bioactive H 2 Se, which may be unfeasible in patients in whom antioxidant defenses are already strained . Inorganic selenide salts (e.g., Na 2 Se and NaHSe) are short-lasting H 2 Se donors, which not only may engender toxicity but also fail to mimic the slow and well-regulated in vivo H 2 Se generation.…”