Is α‐lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity

Abstract

SummaryThe chemical reduction and oxidation (redox) properties of a-lipoic acid (LA) suggest that it may have potent antioxidant potential. A significant number of studies now show that LA and its reduced form, dihydrolipoic acid (DHLA), directly scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) species and protect cells against a host of insults where oxidative stress is part of the underlying etiology. However, owing to its limited and transient accumulation in tissues following oral intake, the efficacy of nonprotein-bound LA to function as a physiological antioxidant has been questioned. Herein, we review the evidence that the micronutrient functions of LA may be more as an effector of important cellular stress response pathways that ultimately influence endogenous cellular antioxidant levels and reduce proinflammatory mechanisms. This would promote a sustained improvement in cellular resistance to pathologies where oxidative stress is involved, which would not be forthcoming if LA solely acted as a transient ROS scavenger.

Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response

“…A low, physiological dose of LA (50 μM) [21] resulted in a 2.5-fold (P<0.05) increase in protein levels of Nrf2 in the nuclei of HepG2 cells within 1 hr after treatment (Figure 2A). Nrf2 levels remained elevated even 24 h following LA treatment in HepG2 cells, but did not result in changes to Nrf2 transcript levels up to 8 hrs after the stimulus relative to vehicle treatment (Figure 2B).…”

Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes

“…Therefore, they can elicit their antioxidant actions in both the cytosol and plasma membrane in contrast to vitamin C (which is lipophobic) and vitamin E (which is lipophilic). Another important action of LA and DHLA, is the ability to reduce the oxidized forms of other antioxidants such as GSH; GSH being one of the most important low molecular weight cellular antioxidants, buffering the thiol redox state (Petersen Shay et al 2008). …”

Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways

“…The dithiol compounds, a-lipoic acid (1,2-dithiolane-3-pentanoic acid; LA) and dihydrolipoic acid (DHLA), were chosen because they terminate not only a number of ROS and reactive nitrogen species (RNS), but also chelate transition metals in vitro (Packer et al 1995;Smith et al 2004). In addition, they serve as modulators of anti-inflammatory and antiapoptotic signaling pathways (Shay et al 2008). Furthermore, LA has an advantage over another common thioreductant, NAC, because it is bioeffective in a micromolar range, whereas millimolar NAC is required to obtain similar effects (Flora 2011).…”