Role of dehydroepiandrosterone sulfate as a scavenging antioxidant: the evidence from Caenorhabditis elegans’ nervous system under hypoxia

Abstract

In nature, changes in O2 levels occur frequently. An inadequate supply of oxygen often happens in living systems, which induces an imbalance between oxygen entering cells and their oxygen demand to produce energy. The condition is known as hypoxia. Although hypoxia takes place in multiple physiological processes, it can be a primary cause of cellular injury and death (Nystul and Roth, 2004). Consequently, cells and tissues are habitually at risk, and they have developed many strategies to cope with low oxygen levels leading to pathological conditions (Fawcett et al., 2015). These adaptative responses to hypoxia though not entirely understood, seem to be evolutively conserved. Notwithstanding these responses, hypoxia can still have harmful effects. It should consider that the sensitivity of cells and organisms to hypoxic damage varies widely, and injuries in the central nervous system (CNS) are likely severe. In the case of the GABAergic system, hypoxia induces changes in mammal models. Neuroactive steroids have shown protective effects against hypoxic processes in mammals, but their exact mechanism of action at the cellular level is unclear. Neurosteroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) have putative indirect and direct mechanisms underlying their protective effects. The indirect mechanism implies the conversion of DHEA into androgens or estrogen. Direct mechanisms include interacting with neurotransmitter receptors, prompting neurogenesis via non-classic steroid receptors, or having antioxidant properties and antiinflammatory activities (Allolio and Arlt, 2002). In any case, it is complicated to assure these underlying mechanisms of action, particularly in mammal studies, because of their wide variety of targets in signal transduction pathways, in addition to transport and bioconversion processes. Recently, employing a model of chemical hypoxia in the nematode Caenorhabditis (C.) elegans, we demonstrated a neuroprotective activity of DHEAS probably associated with its chemical structure, functioning as a chain-breaking antioxidant (Gallegos-Saucedo et al., 2020).